post op phantom limb

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• Residual limb pain

Residual limb pain, sometimes called stump pain, is a type of pain felt in the part of a limb that remains after an amputation. It occurs in about half of people who have had an amputation. It may occur soon after the surgery, often within the first week, but may also last beyond healing. Residual limb pain usually isn't severe, but it may feel:

In some people, the residual limb may move uncontrollably in small or significant ways. Residual limb pain is different from phantom pain, which is pain that seems to come from an amputated limb. But residual limb pain and phantom pain often occur together. Research shows that more than half of people with phantom pain also have residual limb pain.

Residual limb pain may be caused by:

• Problems in the bone or the soft tissue
• Poor blood supply to the limb
• Problems with the fit or use of a prosthesis
• Benzon HT, et al., eds. Phantom limb pain. In: Practical Management of Pain. 5th ed. Philadelphia, Pa.: Mosby Elsevier; 2014. https://www.clinicalkey.com. Accessed Sept. 7, 2018.
• AskMayoExpert. Amputation management (adult). Rochester, Minn.: Mayo Foundation for Medical Education and Research; 2018.
• Kalapatapu V. Lower extremity amputation. https://www.uptodate.com/contents/search. Accessed Sept. 7, 2018.
• Pain in the residual limb. Merck Manual Professional Version. https://www.merckmanuals.com/professional/special-subjects/limb-prosthetics/pain-in-the-residual-limb#v21361465. Accessed Sept. 7, 2018.
• Freedman MK, et al. Amputation-related pain. In: Challenging Neuropathic Pain Syndromes: Evaluation and Evidence-Based Treatment. St. Louis, Mo.: Elsevier; 2018. https://www.clinicalkey.com. Accessed Oct. 25, 2018.
• Benzon HT, et al., eds. Postamputation pain. In: Essentials of Pain Medicine. 4th ed. Philadelphia, Pa.: Elsevier; 2018. https://www.clinicalkey.com. Accessed Oct. 25, 2018.
• Sandroni P (expert opinion). Mayo Clinic, Rochester, Minn. Oct. 30, 2018.
• Nerve blocks. Radiological Society of North America. https://www.radiologyinfo.org/en/info.cfm?pg=nerveblock. Accessed Nov. 6, 2018.
• Petersen BA, et al. Phantom limb pain: Peripheral neuromodulatory and neuroprosthetic approaches to treatment. Muscle & Nerve. In press. Accessed Nov. 6, 2018.

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Article Contents

Pain following amputation, management of acute stump pain, phantom limb pain, pathophysiology, prevention and treatment, pharmacological treatment, salmon calcitonin, nmda antagonists.

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Pain after amputation

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MJE Neil, Pain after amputation, BJA Education , Volume 16, Issue 3, March 2016, Pages 107–112, https://doi.org/10.1093/bjaed/mkv028

Good quality postoperative analgesia is essential for limb amputation.

Pain management after amputation can be challenging due to the presence of mixed nociceptive and neuropathic pain.

Thorough pain assessment is required to establish the aetiology of post-amputation pain.

Prolonged analgesia via continuous perineural blockade provides optimal analgesia for early management of stump and phantom pain.

Salmon Calcitonin and Memantine can be useful in the acute management of phantom limb pain.

Amputation of a limb is one of the oldest recorded surgical procedures. Traumatic amputation and use of a prosthesis is found written in Sanskrit texts dating from 1800 to 3500 BC. Today, amputation remains a commonly performed surgical procedure with ∼5500 lower limb amputations carried out in England alone every year. 1 Complications from peripheral vascular disease and diabetes are the leading medical causes of amputation although worldwide a vast number are as a consequence of trauma. Internationally, accurate numbers of limb amputations performed are very difficult to estimate as there is no recognized database or organization collecting this information.

Regardless of the indication for surgery, pain management after amputation is challenging. Amputation of a limb is one of the most severe pains in the human experience. This is attributable to the magnitude of the tissue injury involved and the varying loci of centres responsible for pain generation; comprising peripheral, spinal, and cortical regions. Pain after amputation involves nociceptive pain, due to bone and soft tissue injury, and neuropathic pain from direct neural trauma and central sensitization. This leads to a complicated, mixed, form of pain and a highly varied array of different postoperative pain syndromes. The burden of pain after amputation is therefore considerable, not just in the short term, but also in the years and decades after surgery. Severe post-amputation pains from phantom limbs have been recorded in survivors from World War II, some 50 yr after loss of a limb. 2

Pain management is often complicated in surgical amputees due to the presence of polypharmacy and severe co-morbidity including ischaemic heart disease and renal compromise. Furthermore, for these reasons, amputees remain a high-risk patient group with a 22% thirty-day mortality from emergency surgery.

This article will discuss the different pain phenomena encountered after limb amputation and its management. This will include stump pain, acute phantom limb pain, and back pain. Different perioperative treatment modalities will be discussed aiming to inform practice in achieving optimal acute pain control and potentially preventing the chronicity of acute pain.

Acute pain management has been identified as a key priority in the management of patients undergoing amputation by a recent NCEPOD report. In achieving good quality analgesia it is important to strike a balance between effective pain control and excess morbidity as a result of interventional or pharmacotherapy. However, failure to optimize acute pain control not only leads to a detrimental pathophysiological stress response but impacts on a patient's psychology, functional recovery and predisposes to chronic stump and phantom pain.

A number of different pain syndromes can present after amputation. These shall be discussed as stump pain, phantom pain, and mechanical pain. It should be borne in mind however that each pain rarely exists in isolation and frequently contribute to one another. A full assessment must therefore be made of each patient to try and identify the predominant pain at the time.

The immediate aftermath of limb amputation in the first postoperative days is dominated by surgical wound pain. This pain is readily identifiable and confined to the surgical site. Surgical stump pain is often described as sharp, aching, and severe. It is primarily a nociceptive form of pain due to the extensive tissue trauma involved, however, the inevitable direct neural injury that occurs results in a significant neuropathic component to the presentation. This neuropathic component may be part of the reason for the relative analgesic failure seen if single modality, anti-nociceptive, pharmacotherapy is used.

In the absence of regional anaesthesia, the severity of the stump pain requires management with strong opioids as a baseline. Opioids used in isolation are however often insufficient and require to be taken in such quantities as to cause significant sedative side-effects. Consequently, adjuvant analgesics such as i.v. Ketamine are frequently required.

Acute stump pain would be expected to resolve in the first few weeks after amputation, however, ∼10% of patients will go on to experience persistent stump pain 3 although some studies quote a far higher incidence than this. The differential diagnosis for persistent stump pain is varied. It is therefore important to take a full history as well as visually inspecting, palpating, and performing sensory testing of the stump to identify any tender points, dysaesthetic areas and any possible pathology.

Some potential causes of persistent stump pain are listed in Table  1 .

Aetiology of persistent stump pain

Three particular causes of persistent stump pain are worth specific mention; infection, neuroma, and heterotopic ossification.

Infection is relatively common after amputation. Higher rates of infection are seen in below knee compared with above knee amputations, in diabetic patients, patients with poor nutritional status, ongoing vascular compromise or if there has been pre-existing infection in the amputated limb. Infections at a stump include cellulitis, abscess, or osteomyelitis. Clinical evidence of infection includes erythema, swelling, purulent exudate, or wound breakdown.

If a stump infection is suspected it must be treated early and aggressively. Baseline investigations include white cell count, CRP, blood and wound cultures. X-ray, magnetic resonance imaging (MRI), or bone scan may be required if osteomyelitis is suspected. Prolonged antibiotic treatment is often required. If a stump infection is not controlled, early serious systemic sepsis can result in addition to wound dehiscence that occasionally requires surgical debridement or revision of a stump to a higher level.

Stump neuroma

After a nerve has been severed, an intense immune-cell mediated inflammatory reaction is observed. This of itself causes pain and peripheral sensitization but also initiates a process by which free endings of unmyelinated A-delta and C-fibres sprout to form a tangled end at the cut surface of the nerve bundle. Neuromas display altered sodium channel function with reduced activation thresholds and spontaneous firing. This leads to unprovoked pain and contact sensitivity in the region of the neuroma. There is a close association between the presence and severity of stump neuroma pain and phantom limb pain.

Neuromas take time to develop and are not usually seen in the first few weeks after amputation. Features suggestive of neuroma formation include a focal point of pain at the stump, spontaneous pain, and localized sensory changes.

Heterotopic ossification

This is a phenomenon rarely considered as a cause for acute or persistent stump pain. It has only been characterized recently due to the upsurge in patients suffering traumatic amputation in military conflict. Heterotopic ossification essentially involves the deposition of calcium in the soft tissues of the stump. The incidence is unknown in medical amputees but has been found in up to 63% of patients after traumatic amputation. 4 Interestingly, the presence of traumatic brain injury significantly increases the risk of heterotopic ossification.

There is no definitive means of preventing heterotopic ossification. Some centres have used a bisphosphonate (such as Etidronate) to prevent heterotopic ossification but good evidence for this practice is lacking. Non-steroidal anti-inflammatory medication may be helpful but this class of drug is frequently contra-indicated in many amputees. COX-2 inhibitors may offer a slightly safer alternative although, again, there is no good evidence to support routine use of these drugs in this circumstance.

In the sub-acute or chronic setting, a patient presenting with persistent stump pain should have this diagnosis considered and investigated by way of an X-ray of the stump. There are no well described, definitive, treatments for this condition. Heterotopic ossification can be managed conservatively in many cases but further surgery may be indicated if ossification is severe.

Systemic opioids delivered via patient controlled analgesia (PCA) are commonly used for post-amputation pain management in the acute phase. This can provide reasonably satisfactory analgesia and has a number of advantageous features including ease of titration, reliable systemic delivery, minimal invasiveness, and relatively low associated morbidity. Morphine is commonly used however there is no good evidence to indicate it is superior to any other opioid in the circumstance. The patients' clinical condition or past experience may make another opioid more preferable, e.g. fentanyl may be more appropriate if there is significant renal impairment (eGFR <30 ml min −1 1.73 m −2 ).

Acute stump pain, in the absence of other pathology, would normally be expected to have subsided by the time of discharge from hospital such that strong opioids were no longer required. If stump pain is still severe enough to require strong opioids at the point of discharge, continuing causative factors or pathology should be sought and referral made to Out-patient Pain Services for follow-up and monitoring of analgesia.

Other pharmacological modalities are often used in the management of acute stump pain. Ketamine given via a low-dose continuous i.v. infusion at up to 15 mg h −1 is often helpful. Gabapentinoids are frequently utilized and present a rational choice due to their effect on nociceptive as well as neuropathic pain. Pregabalin is a good choice due to its superior pharmacokinetic profile with more reliable enteric absorption, faster onset, and relatively low incidence of side-effects. A starting dose of 25–75 mg per day is recommended depending on renal function and clinical condition.

The gold standard for management of post-amputation acute stump pain is regional anaesthesia. This can be accomplished either with central neuraxial blockade, usually via an epidural infusion, or peripheral nerve block. It should be noted that there is no good evidence to indicate that commencing central neuraxial or perineural blockade for a prolonged period before operation confers any advantage in terms of minimizing acute, or chronic, stump or phantom pain. Preoperative regional anaesthesia is only clearly indicated in cases of severe, treatment refractory, ischaemic pain before re-vascularization or amputation. In this circumstance regional anaesthesia is highly effective in controlling pain, alleviating distress, decreasing opioid related morbidity and even improving peripheral perfusion.

Epidural analgesia

This has been the most widely discussed and researched technique for post-amputation analgesia. For management of stump pain, epidural analgesia can be effective and versatile offering a number of advantages over systemic pharmacological techniques. For example, epidural analgesia can be started before operation to provide analgesia for ischaemic pain; can be converted to provide anaesthesia for surgery and continued after operation.

Opioid related morbidity, particularly respiratory complications, can be minimized with central neuraxial blockade but there has been no consistent or clear advantage demonstrated to date on preventing chronic pain, including phantom pain, with the use of epidural analgesia for amputation. This is somewhat surprising but methodological problems with the design of many studies, particularly the early discontinuation of epidural analgesia after operation, is important in interpreting the validity of these findings.

Although epidural analgesia can be very effective for the management of acute surgical pain, there are limitations to the technique in this patient group. Specifically, many vascular patients require therapeutic anti-coagulation thus either contra-indicating or substantially increasing the risk of epidural haematoma. Furthermore, epidural analgesia can have a failure rate approaching 10%; the potential for infection is higher with prolonged use of epidural blockade particularly in the diabetic population and adequate critical care facilities, staffing and monitoring are required. Consequently, resources may not be available in many hospitals to deliver epidural analgesia safely to this high-risk patient group.

Perineural blockade

Perineural blockade has been a major advance in pain management after amputation. The introduction of ultrasound guided neural blockade has made this technique more reliable particularly when identifying nerve supply to a non-viable limb or after traumatic amputation. Perineural blockade has been effectively utilized by the Armed forces for many years because continuous peripheral nerve block provides a relatively simple and highly effective means of providing prolonged, good quality analgesia, with low monitoring requirements that is virtually free of systemic side-effects.

When instituting regional anaesthesia for the lower limb, the relevant nerves should be blocked depending on the level of amputation. For below knee amputation a sciatic nerve block is sufficient while for above knee amputation, both the femoral and sciatic nerves should be targeted. Ideally, nerve blocks should be instituted immediately before surgery in addition to either general or central neuraxial anaesthesia. Anaesthetic placement of a perineural catheter may not be possible in all circumstances in which case a surgically placed sciatic catheter should be sought to be sited under direct vision providing there are no significant concerns regarding on-going local infection.

For postoperative analgesia perineural blockade can be initiated with a bolus dose and continued with elastomeric pumps delivering local anaesthetic at up to 10 ml h −1 . Ropivacaine is a good choice due to low cardiotoxicity; an important consideration particularly if two nerve catheters are placed. A typical perineural infusion lasts 40 h and is often discontinued at this point once the elastomeric pump runs out. For management of wound pain, this is too early as nociceptive pain is still maximal inside the first 72 h. Perineural blockade should be extended beyond 72 h whenever possible. Experience at our hospital indicates that perineural blockade can be continued safely to 80 h or more before discontinuing. This technique provides excellent analgesia in the first crucial days after amputation with low associated morbidity, results in minimal systemic opioid requirements and has a very low incidence of catheter related infections.

Phantom limb pain is the most widely known post-amputation pain syndrome. The first written record of phantom limb pain dates to 1462 when Ambrose Paré, a French surgeon, reported the phenomenon in his book Treatise on Surgerie. It is a phenomenon that has largely remained a medical curiosity over the centuries as it defied satisfactory explanation and effective treatments remained elusive. It is only in recent years that we are gaining a clearer insight into this problem and how to manage it.

Phantom limb pain occurs in up to 80% of amputees. At least 75% of patients who develop phantom pain do so within the first week after amputation. The natural history of phantom pain is then variable. Many patients will show gradual improvement of phantom pain within the first year and some will resolve completely. Many patients however will have phantom pain for life.

Like other chronic post-surgical pain syndromes there are no definitive predisposing factors but some circumstances do make the chances of developing phantom pain higher. These are listed in Table  2 .

Risk factors for developing phantom limb pain

There is no clear difference in the incidence of phantom pain between the sexes and psychological factors such as depression or anxiety are not predictive. It is important to note however that patients with significant psychological risk factors do tend to report more severe phantom pain with higher levels of disability and reliance on medication.

Phantom limb pain is typically felt in the distal extremity of the absent limb. Pain characteristics vary but are often described as being cramping, burning, or shooting in nature. It is not uncommon to observe that if a patient experiences severe pain in a limb before operation then the same pain will be experienced after removal of that limb. Phantom pains are usually episodic occurring in short bouts ranging from a few seconds to many hours. It is the minority of patients who have severe and unremitting phantom pain.

Patients may report other phenomenon from the missing limb such as tingling or itching. These non-painful phenomena are termed phantom sensations. Patients should be informed that these are normal and reassurance is provided. The phantom limb may also be felt to be in a different position, shape or size to the missing limb. Telescoping, where sensation from a missing extremity migrates in perceived position towards the stump, can occur but this is usually a finding in more established cases.

The precise mechanisms underlying phantom limb pain have been difficult to accurately elucidate. This is likely to reflect the fact that anatomically different pain centres can be involved in producing the phenomenon with one or more loci contributing at any one time. There are however three key areas that are implicated in phantom pain.

Peripheral nerves

Many patients presenting for amputation will already have a damaged and sensitized peripheral nervous system due to ischaemia. Further neural injury from surgical trauma leads to an inflammatory reaction and the release of pro-nociceptive factors such as cytokines, prostaglandins, and substance P. These factors cause a decrease in activation thresholds from nociceptors and spontaneous discharge leading to further sensitization. These changes occur in afferent nociceptive pathways emanating from the absent limb.

It is likely that during the early postoperative phase it is the intensity of the afferent peripheral nociceptive stimulus that initiates phantom pain and results in the changes seen subsequently upstream in the central nervous system (CNS). Neuroma formation is frequently cited as being the cause of phantom pain. While this may be true in the sub-acute or chronic phase, within the first week of amputation when the majority of phantom pains first present, a neuroma would not have had time to develop so cannot be responsible for acute phantom pain.

Spinal cord

The intense nociceptive barrage from the peripheral nervous system has a profound effect on pain pathways at the spinal cord. At this level the dorsal route ganglion is an important site as afferent pain signals can be substantially modified, either attenuated or enhanced. The N -methyl- d -aspartate (NMDA) receptor seems to be particularly important in this process for both modifying nociceptive signals and facilitating CNS plasticity. Specifically, the NMDA receptor is involved in the phenotypic switch and cross sprouting that occurs in afferent nerve fibres after amputation. This results in afferent non-painful stimuli being felt as painful and the widening of receptive fields from one neural pathway resulting in sensitivity extending beyond the dermatomal distribution of one nerve.

Somatosensory cortex

Considerable attention has been focused on the somatosensory cortex as a source of phantom limb pain. It has long been suspected that cortical structures were implicated in the generation of phantom limb pain however it has not been until the introduction of functional MRI scanning that this has been confirmed. The cortical changes after amputation are complex but not unique to phantom pain. Similar cortical reorganization is also seen in cases of Complex Regional Pain Syndrome and lower back pain.

In essence the cortical changes involve a compensatory migration into the representation of the absent limb from adjacent regions of the somatosensory cortex. This can be inferred clinically as patients with upper limb amputation can experience exacerbations of phantom pain on touching their face or, in the lower limb, experience phantom pain with a full bladder.

Many therapies have been studied over the decades for phantom pain and are too numerous to cover in detail within the scope of this article. Only the most pertinent and promising interventional and pharmacological treatments are discussed. The use of strong opioids in this circumstance does require special mention. It must be emphasized that strong opioids have a very limited role in the management of either acute or chronic phantom limb pain. Strong opioids initiated to manage wound pain should not be continued without very good reason and with proven efficacy on a case-by-case basis for the management of phantom pain.

Perineural blockade provides excellent analgesia for surgical stump pain and in doing so can attenuate peripheral and central sensitization that may either prevent, or at least minimize, the impact of phantom pain. Many studies looking at the use of regional anaesthesia in the prevention of phantom limb pain discontinue neural blockade within 48 h of surgery. When considering that stump pain and the inflammatory process is still at its peak at this time, as stated previously, it is clear this is far too soon to discontinue therapy.

An interesting study by Borghi et al. 5 demonstrated a very significant reduction in the incidence of phantom limb pain with the use of prolonged perineural blockade. They reported only a 2% incidence of phantom pain by continuing neural blockade for up to 80 days after amputation. Prolonging perineural blockade to this extent is unlikely to be feasible in most hospitals but enhancing existing practice is possible.

In our hospital, continuous perineural blockade is commenced perioperatively with 400 ml of Ropivacaine 0.2% infused via an elastomeric pump at 10 ml h −1 if a single catheter is used or 5 ml h −1 per catheter if two infusions are required for above knee amputations. Perineural blockade is continued for a minimum of 80 h after amputation to get a patient beyond the crucial first days of maximal pain in order to minimize sensitization. Local experience indicates this is probably the single most important technique for acute pain management after amputation and is crucial in decreasing the likelihood of developing significant phantom limb pain.

Tricyclic antidepressants

This family of medication is frequently utilized in the management of neuropathic pain, however, they have little role in the acute management of phantom limb pain. Tricyclic antidepressants are of limited utility as they are frequently contra-indicated in surgical amputees due to patients' concurrent co-morbidities; the analgesic effect is of slow onset, of poor efficacy and side-effects frequently preclude dose titration.

Gabapentinoids

Gabapentinoids are agonists at the alpha-2-delta subunit of voltage dependent calcium channels and GABA B receptors in the CNS. This class of medication is increasingly recognized for its anti-nociceptive and anti-neuropathic effects. Gabapentinoids are an integral part of many enhanced recovery pathways for their opioid sparing effects and there is increasing evidence they can help prevent the development of chronic post-surgical pain.

Gabapentinoids have a good safety profile, few drug interactions, are well tolerated and have efficacy in both neuropathic and nociceptive pain. With regard to phantom limb pain the majority of published evidence only examines the use of Gabapentin in chronic, established, cases. Only one study by Nikoljsen et al. 6 examined early postoperative use of Gabapentin after amputation but did not find any benefit for stump or phantom pain. No studies to this time have been done examining Pregabalin in this context. Although there is no conclusive evidence, a Cochrane review identified a ‘trend towards benefit’ from Gabapentin in the management of phantom pain. 7

Increasingly compelling evidence is emerging regarding the use of Gabapentin, and Pregabalin in particular, for preventing chronic post-surgical pain. Combining these two strands of evidence indicates that it is reasonable to initiate therapy with a Gabapentinoid perioperatively, as the clinical condition allows, continuing after operation for as long as felt to be clinically necessary.

Salmon calcitonin is a neuropeptide with a novel analgesic action. Its exact mechanism of action is not well defined but is postulated to be due to a combination of altered β-endorphin production, inhibition of prostaglandin and cytokine production and modulation of central serotonergic pathways. It is only available in parenteral form in the UK.

Salmon calcitonin has been found to have analgesic efficacy in a diverse range of pain disorders including pain from spinal cord injury and vertebral fractures. It was however first serendipitously found to have an analgesic action on phantom limb pain in a number of early case reports. A small study by Jaeger confirmed the benefits of a short treatment course of salmon calcitonin on phantom limb pain the effects of which were still evident on follow-up 1 yr later. 8 Unlike many therapeutic agents in pain management salmon calcitonin, when successful, abolished phantom limb pain.

Despite these promising early results, salmon calcitonin has seldom been studied and is infrequently utilized in acute pain management. Due to its good safety profile, low incidence of side-effects, and efficacy it should be considered for early treatment of acute phantom limb pain. A dose of 100 IU per day given subcutaneously as a treatment course for 5–7 days should be considered for acute presentations.

Clonidine is an agonist at α2-adrenoceptors which are primarily located in the CNS and are involved in central control of the cardiovascular system. α2-Adrenoceptors are also expressed on macrophages at the site of inflammation where they have a role in the expression of pro-inflammatory cytokines. Perineural clonidine has been found to prolong and enhance regional anaesthesia and reduce mechanical hypersensitivity after nerve injury.

There are no well conducted studies specifically examining the use of clonidine as an adjuvant to perineural blockade for amputation. Extrapolating the best evidence available and clinical experience indicates that the addition of clonidine to a continuous perineural infusion at a dose of between 10 and 20 μg h −1 after amputation can be safe and effective. In our practice, perineural clonidine is reserved for patients whose block has not been complete or who are judged to be very high risk of severe stump or phantom pain.

Ketamine is the most widely used NMDA antagonist. It has specific anti-neuropathic, anti-nociceptive and anti-hyperalgesic properties. It is commonly used perioperatively for amputation surgery but it does not prevent the development of phantom limb pain. Rather, Ketamine can decrease the severity of phantom pain experienced. I.V. Ketamine is probably the best means of administration as it ensures reliable systemic delivery (oral Ketamine has a bio-availability of only 20–40%), minimizes side-effects and ensures continuous blockade of the NMDA receptor in the crucial early postoperative period.

Memantine is another NMDA antagonist that is seldom considered in pain management. It has different binding characteristics at the NMDA receptor compared with Ketamine and, crucially, is relatively free of the psychotropic effects that frequently limit the use of Ketamine. Memantine has no active metabolites, is renally excreted and preferentially accumulates in the CNS where it has a half-life of 80 h. All these properties are advantageous in treating pain in amputees.

Memantine has been studied when given perineurally and orally. The conclusions reached from these studies and in subsequent reviews dismissed Memantine on the grounds of lack of statistical significance in treating phantom pain. Crucially, Memantine did display considerable clinical significance in these studies and the evidence available needs to be re-evaluated with this in mind. Local experience indicates Memantine is generally well tolerated and efficacious in the management of phantom pain.

Back pain is a very common yet under recognized and seldom studied post-amputation pain problem. Back pain can arise de novo after amputation or pre-exist and be exacerbated by loss of a limb. Back pain may also occur as a result of prolonged bed rest after surgery but is more frequently encountered during the early rehabilitation phase during weight bearing on a prosthesis. Considerable bio-mechanical changes occur in the lower back and pelvis as a result of altered weight and force distribution and different muscle utilization.

Assessment of the clinical characteristics of back pain is essential to exclude any specific spinal or disc pathology. Following exclusion of spinal pathology, e.g. disc herniation or discitis, treatment can proceed on empirical grounds with attention paid to adequate prosthetic fitting and physiotherapy. Pharmacological management should comprise simple analgesics, anti-inflammatories (where clinically appropriate), middle strength opioids, and non-benzodiazepine-based neuromuscular blocking agents. TENS machines and acupuncture are also useful in this setting. Strong opioids should be avoided if at all possible.

Post-amputation pain management remains a challenging area of clinical practice. A wide variety of pain problems present after operation which need careful clinical assessment to differentiate. Despite considerable advances in surgical and anaesthetic practices, pain related morbidity remains high after amputation.

The evidence base for optimal analgesic management is incomplete but it is wrong to use this reason as a basis for persevering with conventional treatment strategies that have proved ineffective. Best evidence, clinical experience, and pragmatism all indicate prolonged perineural blockade is the best analgesic technique post-amputation to attenuate both nociceptive and neuropathic pain. Continuation of perineural blockade for a minimum of 72 h post-amputation is essential in achieving this goal.

A multi-disciplinary, multi-modal approach to pain management must be emphasized comprising assessment and engagement in pain control from all team members involved in the care of amputees. Early treatment of acute phantom limb pain with novel analgesic agents such as salmon calcitonin and Memantine may offer the best chance of success to prevent chronicity alongside active physical and rehabilitation therapy.

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Management of Post-Amputation Pain

Affiliations.

• 1 Department of Orthopaedic Surgery, Alpert Medical School of Brown University/Rhode Island Hospital, Providence, RI.
• 2 Chief, Division of Pediatric Orthopedics, Hasbro Children's Hospital; Associate Professor of Orthopaedic Surgery, Alpert Medical School of Brown University/Rhode Island Hospital, Providence, RI.
• PMID: 32357588

Introduction: The prevalence of amputation and post-amputation pain (PAP) is rising. There are two main types of PAP: residual limb pain (RLP) and phantom limb pain (PLP), with an estimated 95% of people with amputations experiencing one or both. Medical Management: The majority of chronic PAP is due to phantom limb pain, which is neurogenic in nature. Common medications used include tricyclic antidepressants, gabapentin, and opioids. Newer studies are evaluating alternative drugs such as ketamine and local anesthetics. Rehabilitation Management: Mirror visual feedback and cognitive behavioral therapy are often effective adjunct therapies and have minimal adverse effects. Surgical Management: Neuromodulatory treatment and surgery for neuromas have been found to help select patients with PAP.

Conclusion: PAP is a complex condition with mechanisms that can be located at the residual limb, spinal cord, and brain - or a combination. This complex pain can be difficult to treat. The mainstays of treatment are largely medical, but several surgical options are also being studied.

Keywords: amputation; phantom limb pain; post-amputation pain; residual limb pain.

Publication types

• Amputation, Surgical / adverse effects
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• Pain Management / methods*
• Pain Measurement
• Phantom Limb / etiology
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INTRODUCTION

Factors that predict the need for lower extremity amputation in patients with extremity ischemia include tissue loss, end-stage kidney disease, poor functional status, and diabetes mellitus. Patients with diabetes have a 10-fold increased risk for lower extremity amputation compared with those who do not have diabetes. Amputees with diabetes are more likely to be severely disabled, experience their initial amputation at a younger age, progress to higher-level amputations, and die at a younger age compared with patients without diabetes [ 3 ].

The indications and techniques for lower extremity amputation, postoperative care, complications, and outcomes are reviewed here. Techniques for performing lower extremity amputation are discussed elsewhere. (See "Techniques for lower extremity amputation" .)

TERMINOLOGY

Amputation performed without an attempt at limb salvage (eg, revascularization, bony repair, soft tissue coverage) is termed primary amputation, whereas amputation following a failed attempt at revascularization is termed secondary amputation. Traumatic amputation refers to limb loss that occurs in the field at the time of injury.

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Home > Books > Pain Management - Practices, Novel Therapies and Bioactives

Amputation Pain Management

Submitted: 04 June 2020 Reviewed: 01 September 2020 Published: 21 September 2020

DOI: 10.5772/intechopen.93846

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Considerable number of new amputations yearly in the United States and internationally represent considerable population experiencing pain that is not just acutely from surgical insult but chronically that is related to phantom limb pain and residual limb pain. This chronic pain can last from weeks to years in these patients and lead to other debilitation such as depression, anxiety and even opioid addiction. Early interventions help lessen long-term pain for these patients. These interventions include nerve blockade as well as multi-modal therapy. Understanding the pathophysiology of the pain experienced by these patients will better allow any provider to care for these patients effectively and help alleviate chronic pain in the long term.

• phantom pain
• neuropathic pain

Author Information

Melinda s. seering *.

• University of Iowa, Iowa City, USA

Sangini Punia

*Address all correspondence to: [email protected]

1. Introduction

Patients with amputations can be found living fulfilled lives. We have all seen them running marathons, in the Olympics, surfing, climbing Mount Everest and even as an MLB pitcher. However, most just want to lead normal lives and be the best parents, siblings, friends, or co-workers they can be. They want to return to their job and function in their daily lives as they did before. Recovery from an amputation is not immediate and takes significant time. Recovery time from amputation is usually prolonged. Wound healing is done in 4–8 weeks, but the prolonged mental, emotional, and physical recovery afterwards takes much longer and will be different for everyone. One of the limiting factors for recovery from an amputation is pain.

In looking at data from the Amputee Coalition, there are 185,000 in the United States every year. This means that an average of two million people is living with an amputated extremity in the United States alone [ 1 , 2 , 3 ]. Other data to consider is just as alarming; globally, there are 1 million amputations annually. This is an estimated 1–2 amputation per minute. Lower limb amputations are the most common, with most being due to vascular disease. 85% of lower limb amputations are preceded by a foot ulcer. About half of the people with diabetes who get a lower limb amputation will receive a second amputation [ 4 ]. African American populations are four times more likely to get an amputation than Caucasian [ 5 ]. Around a third of these patients have persistent depression and anxiety after their amputation [ 6 ]. Financially, it is noted that amputees have higher healthcare costs and if the amputation was related to vascular disease higher mortality [ 7 ].

All these factors can lead to an unknown fear for a patient undergoing an amputation. Understanding the cause of an amputation first is paramount. This can help guide a plan for better pain control in the perioperative period. The main causes of amputation are progression of disease processes such as peripheral vascular disease (82%) including ischemia and thrombosis. Diabetes and infections such as osteomyelitis and gangrene that is unresponsive to antibiotic treatment. The second major cause is trauma (16.4%). This has a high predominance in upper extremity amputations. Lower extremity amputations with trauma can also be seen with severe fractures that do not heal and frost bites as other causes. Finally, surgical removal of malignancies (0.9%) can result in amputations in upper or lower extremities depending on the location and type of the tumor and growth. Congenital malformations (0.8%) make up the final list for amputation categories [ 1 , 2 ].

It is important as we consider the cause of the amputation and perioperative pain control, we also factor in the amount of time each patient had before surgery for their amputation decision. A diabetic patient that had a long time to make a decision for an amputation may have had considerable time to go through the stages of grief and accept the amputation as opposed to a trauma that did not have this time. Other things to consider are support system that the patient has at home. As discussed, wound healing is brief, but psychological healing will take longer in most and require repeated support and reminders to the patient to keep moving in a positive direction [ 8 ]. In addition to medical management, these patients will need pain-coping strategies and too many these may be a new technique for them in a life altering situation.

2. Pain classification with an emphasis on amputees

Amputation patients have a variety of different pain to consider when treating them in the perioperative setting. The broad classification of this pain is post-amputation pain. However, further classifying it in four categories helps to better understand each pain and how it originates. They are acute post-operative pain, phantom sensations, residual limb pain and phantom limb pain [ 2 , 3 ].

Acute post-operative pain is the pain that most surgical patients experience after any surgery. It is the pain at the surgical incision site related to surgical trauma, swelling and tissue damage. This is usually reported as sharp and stabbing by patients due to nociceptive afferent nerve supply at the surgical site. Patient can also report muscle spasms related to the immobility of the limb or the compression dressing or brace applies to the amputation site after surgery [ 2 , 9 , 10 ].

Phantom sensations are the non-painful sensations arising from the amputated extremity. This is reported by 75% of patients 4 days after the amputations and higher at 6 months. This can be perceived as movement of the prior extremity or portion of the extremity (i.e. toe or finger). The patient can also note temperature changes or position changes or the missing limb. This has also been noted in mastectomies, dental extractions, and enucleations as well, and can also be seen in spinal cord injuries. Many of the phantom sensations are mild and decline but some patients have some degree persistent sensations indefinitely. There are a few patients in whom these sensations progress to severe pain and become problematic, leading to residual limb pain or phantom limb pain. There are reports of phantom sensations that do fade away and they appear to do this in a progressive fashion called telescoping. This is most common in upper extremity amputations where the phantom sensations continue to decrease such that eventually the patient is left with a sensation of the hand on the stump alone instead of distal [ 2 ].

Residual limb pain (stump pain) is the pain localized to the remained affected body segment and can be present for years. Residual limb pain can be of many different modalities as it can be described as deep tissue pain, superficial incision pain and neuropathic in nature. 75% of patients will experience a component of this chronically after surgery [ 11 ]. Neuropathic pain will be described as burning and electric in nature. Some patient may even become hyperalgesia or have allodynia on the stump site. This may lead to difficulty with prosthetic fitting for the patient. This pain is usually noted early in recovery. There are causes of increased stump pain: infection, stump neuroma, heterotopic ossification [ 9 ]. These should be assessed with prolonged or increased stump pain as these are easily treatable. Infection is not uncommon in these patients due to high prevalence of diabetes and peripheral vascular disease. This should be assessed and treated with antibiotics accordingly to prevent sepsis and wound dehiscence. Stump neuromas occur when the severed nerve at the amputation site have an inflammatory mediated immune reaction. This can cause pain, but it can also cause unmyelinated A and C fibers to form around the nerve. Neuromas develop over time and usually are characterized by point pain on the stump and sensory changes. Heterotopic ossifications usually occur later after amputation as well. These are calcium deposits that occur in the soft tissue of the stump. These ossifications occur much higher in traumatic amputations. There is some association with traumatic brain injury and the risk of this occurrence as well [ 2 , 3 , 12 ].

Phantom limb pain was first described in 1462 by French Surgeon, Ambrose Pare’ [ 13 ]. However, it was not until 1871 that Silas Weir Mitchell, a Civil War surgeon, called this phenomenon “phantom limb” [ 2 , 13 ]. Phantom limb pain is an unpleasant or painful feeling in the amputated extremity. 45–85% of patients from amputations can suffer from phantom limb pain [ 9 ]. This can have neuropathic components with burning and electrical shooting pain and nociceptive components of dull, aching, crushing and cramping pain [ 13 ]. There are two times of onset for this pain. One is usually early after amputation in the first month and the second can occur a year after amputation. The further out a patient is from amputation the less likely they will experience this. However, if a patient does begin to experience this, it can last for years. Phantom limb pain does not always have to occur alone and usually occurs with residual limb pain. While residual limb pain may be bothersome early on, phantom limb pain persists and become more bothersome later and tends to last longer. Risk factors for development or prolonging phantom limb pain are found in Table 1 [ 1 , 2 , 3 , 12 , 13 ].

Risk factors for developing or prolonged phantom limb pain.

3. Pain signal transmission

To understand how to treat the pain from amputations, we should first take a moment to review how painful stimulation is transmitted through the body (see Figure 1 ). The human body receives signals from various inputs. If something painful happens to the body such as surgical insult, the damage is registered by nociceptors in the periphery. The distal nerve fibers coalesce and become peripheral nerves. There are pain receptors that present on the neuron and it is connected by an axon to the spinal cord. Transmission from peripheral nerve to dorsal column is obtained by different nerve fibers. These include: A-alpha fibers, the A-beta fibers, the A-delta fibers, and the C fibers. Pain travels on two different nerve fibers: A-delta and C-fibers. A-delta fibers are large myelinated fibers that carry sharp pain, whereas C-fibers are small and unmyelinated fibers that produce dull, slow spreading pain. This signal arrives to the dorsal horn and then travels up via neurotransmitters to the brain. There are a variety of neurotransmitters from the spinal cord to the thalamus. For pain, the most important to consider are Substance P which is an excitatory neurotransmitter for second order neurons in the dorsal horn. This neurotransmitter has been shown to sensitize nociceptors. In addition to pain, Substance P also related to inflammation, cell growth, vasodilation and even mood regulation. Glutamate is also a primary neurotransmitter for pain. It is the main excitatory neurotransmitter in the body. In the brain, glutamate receptors can be both pro-nociceptive as well as anti-nociceptive. This leads to many pain therapies constructed at glutamate. This is used for central sensitization in chronic pain patients [ 14 ]. Once in the dorsal horn, the second order neurons connect with thalamus and other various areas. These can include the somatosensory cortex (physical sensation), limbic system (emotion) and frontal cortex (upper level thinking). This allows a patient to feel and react with pain not just physically but emotionally as well [ 15 ].

Path pathways.

Let us revisit how the various pain pathways are affected during amputation. Phantom pain sensations likely result from changes in the somatosensory cortex. This causes afferent nociceptive stimulation from body parts near the amputation sites (such as face for upper extremity amputation or bladder for lower extremity amputation). Due to this reorganization in the somatosensory cortex and stimulation input, the phantom sensations occur [ 2 , 9 ].

Peripheral nerves likely play a large role in the phantom limb pain and residual limb pain. Damage to distal nerve endings and axons causes inflammation and alteration in neurotransmission along the usual pain pathway. The distal nerve endings will begin to regenerate but there will be non-functional axons, changes in sodium and potassium channels and different input from the spinal cord. Neuromas can form here as discussed previously. This can also result in higher pain due to more catecholamines in circulation due to increased sympathetic discharge [ 2 , 9 ].

There are also spinal cord changes in the dorsal horn related to pain after amputation. The peripheral nerves are no longer able to send the usual signals along the axons to the spinal cord. The brainstem reticular areas therefore do not send inhibitory sensory transmission, so the dorsal horn receives input from this body part as high sensory feedback resulting in pain transmission [ 1 , 2 , 9 ].

These changes in the peripheral and spinal cord need to be considered as we are thinking about treating each patient for amputation pain.

4. Protocol for perioperative caring for amputation patients

It is well understood that effective control of acute post-amputation pain results in decreased risk of development of residual and phantom limb pain [ 16 ]. Perioperative plans need to set up within a multi-disciplinary team, ideally involving surgeon, anesthesia, in-patient acute pain teams, pharmacy, physical therapy, occupational therapy, nutrition, and social work to name a few. The pre-operative optimization is essential to control of acute post-amputation pain and help decrease the risk of development of chronic and phantom pain to help these amputation patients have the best chance for better pain control post-amputation. Thorough pre-operative evaluation is needed to look at co-medical conditions that can be optimized. The patient’s nutrition should be optimized for wound healing as well. Physical therapy and occupational therapy should work with the patient before surgery to improve physical status prior to surgery and make post-operative recovery more successful. Patient should have a pre-operative discussion about post-operative pain management and expectations. This will allow goal setting and help with anxiety the patient may be experiencing.

Patients who struggle with high pain scores prior to amputation may have an elevated risk of developing chronic pain [ 17 ]. Thus, aggressive multimodal analgesic therapy instituted pre-operatively and early in the post-operative period could be beneficial in reducing the incidence of chronic pain. One study found that the presence of depressive symptoms was also a predictor of increased intensity of chronic pain in amputees [ 18 ]. Thus, it may be worthwhile to address these symptoms prior to elective amputation surgery. Patients with a complex history of chronic pain disorders and/or patients having high baseline daily opioid requirements (> 80 mg oral morphine equivalents) should be further selected to undergo a pre-operative appointment with a pain specialist. This appointment should ideally take place around 4 weeks prior to elective amputation with the goal to optimize the patient’s pain regimen pre-operatively, by maximizing non-opioid modalities and reduction of daily opioid consumption if possible. This is done to improve response to opioid therapy in the immediate post-operative period. Thorough patient education and compassionate counseling also play a key role in developing a team relationship with the patient [ 19 , 20 ]. See Figure 2 for full protocol.

Protocol for amputation pain management.

5. Nerve blockade

The current standard of care is pre-operative nerve blockade to prevent peripheral sensitization leading to future onset of phantom limb pain. Successful outcomes necessitate effective communication between the surgeon, anesthesiologist, and the various teams involved in the post-operative rehabilitation of the patient. A consultation with the Acute Pain Service or similar entity that performs peripheral nerve blockade pre-operatively and then follows the patient during their post-operative inpatient course is an important factor in the success in early prevention of acute and chronic pain for these patients.

Most patients that arrive for amputations should be evaluated to receive pre-operative peripheral nerve blocks. If this cannot be done pre-operatively, patients can be evaluated post-operatively for a nerve block. If patients do not require post-operative anti-coagulation that will preclude a continuous peripheral nerve catheter, this would be the preferred nerve block for these patients as this will help with prevention phantom limb pain and chronic post-operative pain [ 3 ]. This can be utilized for 3–5 days. Continuous nerve catheter infusions have been found to decrease post-operative morphine requirements [ 21 ]. However, in addition, there are other factors that may preclude continuous peripheral nerve catheter placement such as infection, and patient factors. If this is the case, single shot peripheral nerve blocks may be utilized. Interestingly, a systematic review and meta-analysis found no difference in pain scores at 24 hours between patients that received a nerve block and those that did not [ 22 ]. However, this study did not look at chronic pain in these patients which is the important component that these nerve blocks are used for [ 9 ].

It is important to understand the anatomy of the amputation site to have successful nerve block placement. For example, a below the knee amputation will rely heavily on a sciatic nerve blockade whereas an above the knee amputation will need blockade of both femoral and sciatic nerves for successful pain control and help with peripheral sensitization for the patient [ 9 ]. For upper extremity amputations, a forearm amputation will be lower in the brachial plexus than an above the elbow amputation or shoulder disarticulation. Tourniquet site is also paramount when planning peripheral nerve block placement. If the catheter is in the surgical site or tourniquet site, there is a risk for dislodgement. It is important to remember this with placement and keep the securement of catheter out of the surgical field. This will take good communication between anesthesia provider and surgeon to achieve this effectively.

It should be noted that epidural blockade may also be used for lower extremity amputation, especially if it will be a bilateral lower extremity amputation. There are studies that show pre-operative epidural placement in amputation patients prevent phantom limb pain due to stopping nociceptive input to the spinal cord [ 3 ]. There is no comparison of epidural to peripheral nerve catheters for lower extremity amputations, but on a practically note, peripheral nerve blockade will allow better mobilization and participation in physical therapy [ 3 ]. In addition, peripheral nerve block does not have the hemodynamic affects that epidural blockade can have [ 23 ].

6. Pharmacology

6.1 opioids.

Opioids remain a favored therapy for pain after surgery. They bind to Mu receptors in peripheral and central nerves as an agonist fashion to produce analgesia. They also can affect phantom limb pain by reducing cortical reorganization [ 10 ]. There is a wide variety to choose from post-operatively as they come in intravenous and oral formulation. Usually initially a parenteral opioid therapy with a patient-controlled analgesia (PCA) is started on post-operative day (POD) zero. Once the patient is tolerating a diet, the PCA is weaned down incrementally and oral opioid therapy is instituted. For opioid tolerant patients, we attempt to calculate their total daily morphine equivalent requirement and base our starting oral dose based on that. The goal is to wean off the PCA completely by 48 hours, coinciding with the discontinuation of other intravenous infusion [ 10 ].

6.2 N-Methyl-D-Aspartate (NMDA) Receptor Antagonists

Ketamine has been studied for post-operative pain. It has been shown that the use of this medication lowers the opioid requirements and reverses opioid tolerance needed for acute post-operative pain [ 24 ]. Ketamine is a noncompetitive NMDA receptor antagonist that targets primarily in the brain and spinal cord. The NMDA receptor is important for synaptic plasticity, central sensitization, amplification of pain signals and opioid tolerance. For amputations, it lowers the dorsal horn sensitization and stops the events that may lead to phantom limb pain and residual limb pain. Important to note, it will not prevent phantom limb pain but will reduce risks of phantom limb pain and residual limb pain [ 9 ]. Ketamine has also been shown to have anti-inflammatory properties which may be effective in the early pre-operative phase. Ketamine infusions can be started in the operating room and continued for 2–3 days post-operatively. Studies show low does ketamine infusions do reduce opioids immediately post-op but there was not a significant reduction in immediate post op pain ratings [ 2 , 3 , 10 ].

6.3 Gabapentinoids

Gabapentin and pregabalin are both anti-convulsant that inhibit alpha 2-delta subunit of voltage-gated calcium channels. They are structural like GABA neurotransmitter, but they are unable to bind to any GABA receptors. In addition to the use with seizures, it has been used for chronic pain, especially neuropathic in nature. Dosages must be titrated slowly, and results are not seen immediately. These doses also must be adjusted for patients with impaired renal function with the help of a pharmacist [ 25 , 26 ]. However, some studies claim that its efficacy to treat phantom limb pain is inconclusive and limited by dose dependent side effects like somnolence and dizziness [ 2 ]. There are other studies more recently that show promise of administration of gabapentinoids for reducing chronic post-surgical pain and this can be exploited to amputees as well [ 3 , 9 , 10 ].

6.4 Acetaminophen

Acetaminophen’s exact mechanism of action is not well understood, but it is thought to reduce the production of prostaglandins in the brain. Prostaglandins are chemicals that cause inflammation and swelling. Acetaminophen relieves pain by elevating the pain threshold, that is, by requiring a greater amount of pain to develop before a person feels it. Acetaminophen administration to amputation patients will help with inflammation and an adjunct to help with post-surgical nociceptive pain, which has been shown to decrease opioid requirements. Acetaminophen dosages will be lowered in patients with pre-existing liver disease [ 27 ]. This will be the most beneficial in the early pre-operative phase. It may be especially beneficially to start prior to the amputation as part of a pre-emptive analgesia. This is thought to protect the central nervous system from noxious insults which result in the patient getting hyperalgesia and allodynia [ 10 , 28 ].

NSAIDs work by inhibiting the activity of cyclooxygenase enzymes (COX-1 or COX-2). By blocking the Cox enzymes, many prostaglandins are not made. This means that there is less swelling and less pain. Most NSAIDs block both Cox-1 and Cox-2 enzymes. For pain, this specifically looks at enzymes that work with prostaglandins for inflammation. Like acetaminophen, these medications work well in the acute perioperative phase for nociceptive pain and reducing opioid requirements. Their use can be limited due to post-operative bleeding concerns. Usually these medications do not help with chronic post amputation pain or phantom limb pain. A short course may be suitable for some patients that have normal renal function; however, we do not advocate for chronic NSAID therapy due to the risks of gastrointestinal bleeding and renal toxicity [ 10 , 23 , 29 ].

6.6 Muscle relaxants

As discussed earlier, acute post-operative pain can have spasmodic pain proximal to the stump site, likely due to tissue inflammation. This can also be present with residual limb pain in some patients. There are a variety of muscle relaxants that can be tried for a short period of time [ 30 ]. If the patient is on opioids, would be cautious of adding a benzodiazepine for muscle relaxant. There is a lack of adequate literature supporting the use of muscle relaxants for post amputation pain.

6.7 Tri-cyclic antidepressants and selective norepinephrine reuptake inhibitors

Anti-depressants are commonly prescribed for chronic neuropathic pain and coexisting depression that accompanies it. These medications work by inhibiting serotonin-epinephrine uptake blockade, NMDA receptor antagonism and sodium channel blockade. These medications have not been shown to work effectively in phantom limb pain in studies. These are not usually done in the perioperative setting as they require careful titration over weeks to months which is better done as outpatient therapy. Side effects of opioids and other modalities may warrant a small dose trial in the perioperative setting to help with uncontrolled acute or phantom limb pain [ 9 , 10 , 31 ].

6.8 Calcitonin

Calcitonin is a hormone secreted by thyroid gland in parafollicular cells. Unlike the parathyroid hormone, its job is to reduce calcium in the blood. There are synthetic forms of this used for chronic pain syndromes. The exact pain mechanism of action is unknown. There are mixed results of phantom limb pain [ 10 ]. The greatest benefit has been shown when it is administered early in the perioperative period; usually within the first 7 days [ 32 ]. There are reports of complete resolution of phantom limb pain with its use [ 9 ].

7. Therapeutic modalities

There are many additional modalities that may be of benefit to amputee patients after the initial perioperative period to help with phantom limb pain and residual limb pain. Many of these involve experienced providers and therapists [ 2 , 10 , 12 , 33 , 34 , 35 , 36 ]. These are summarized in Table 2 .

Therapeutic modalities for chronic amputee limb pain.

8. Conclusions

As patient’s present for amputations, it is important to remember the care for these patients needs to be multi-disciplinary to prevent chronic pain. If perioperative pain plans are developed early and worked on as a team, the patient will benefit the most and have the best chance for success at not having long-term phantom limb pain and/or residual limb pain which adversely impact their quality of life. Psychological preparation is paramount but may not always be accomplished if amputation is needed in emergent or traumatic fashion. These patients can still be cared for effectively in a modified format with high success rate if early post-operative intervention is achieved.

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Correspondence to [email protected]

Dr Michael J.E. Neil, Consultant in Anaesthetics and Pain Medicine

Ninewells Hospital and Medical School, Dundee, UK.

Correspondence to: [email protected]

27TH JUNE 2011

Answer true or false

• Occurs in around 50% of patients after amputation
• Reduces in incidence with time
• Is usually a constant pain
• Is commonly experienced by people with congenitally absent limbs
• Is more common in patients with persistent stump pain
• Non-steroidal anti-inflammatories
• Paracetamol
• NMDA Antagonists
• Sodium channel blockers
• Tricyclic antidepressants

INTRODUCTION

Sensation experienced in an amputated limb was first described in 1551 by Ambroise Paré, a French military surgeon. Subsequently, in 1871 during the American Civil War, the term ‘phantom limb’ was first recorded by the neurologist Silas Weir Mitchell. Despite increased clinical recognition of phantom pain since that time, the mechanisms underlying the phenomenon remain poorly understood. The pathogenesis of phantom pain is complex, including both peripheral and central neural processes and is still the subject of on-going study. Phantom pain is a form of neuropathic pain and, once established, can be extremely difficult to treat.

DEFINITIONS

Following amputation, patients experience a number of different forms of pain. Nociceptive pain in the amputated stump is a normal and predictable response to the surgical insult. Early post-operative perception of non-painful sensations in the amputated limb are common (phantom sensation ) and should be regarded as normal following amputation. However, phantom pain is the perception of pain in the amputated limb.

These different forms of pain must be distinguished by taking a careful history from the patient as treatment varies depending on the predominant nature of the pain described.

• Phantom sensation : Any sensation in the absent body part, except pain.
• Phantom pain: Painful sensations referred to the absent body part.
• Stump pain: Pain localized in the stump.

Phantom sensations

Phantom sensation and phantom pain commonly co-exist. Phantom sensation occurs in most amputees, and is experienced as resembling the pre-amputation limb in shape and size and may include feelings of posture and movement. Patients may describe feelings of warmth, cold, itching, tingling or electric sensations. Phantom sensation usually appears soon after amputation and can last from weeks to years, but is not experienced as being painful.

Some patients also describe the phenomenon of ‘telescoping’. This is where the distal part of the phantom limb is felt to be closer to the stump or within the stump itself. For example, forearm amputees may describe feeling that their amputated hand is attached to their elbow stump. This probably occurs because the cortical magnification of the hand is proportionally over represented on the somatosensory cortex.

Figure 1. The Homunculus; A pictoral view of the somatosensory map with body parts scaled in sizes proportional to their cortical representation (reproduced with permission from Posit Science Corporation)

Phantom pain

Around 60 – 80% of amputees will experience phantom pain in the early post-operative period with the incidence decreasing with time following amputation. The incidence of phantom limb pain appears to be independent of age, gender and level or side of amputation. 75% of patients will develop phantom pain within the first few days after amputation but the first emergence of phantom pain may be delayed and develop several years later. Phantom pain is often regarded as a chronic pain problem lasting for many years following amputation. Several studies, however, have shown a reduction in pain over periods of 2 – 5 years post amputation, although most continue to experience some pain beyond this.

A number of factors have been shown to be predictive of the onset of phantom limb pain post-operatively. Patients found to be most at risk are those who have severe pain in the amputated limb pre-operatively, patients undergoing bilateral amputation and patients with persisting stump pain. The incidence of phantom limb pain is however lower in paediatric amputees and very rare in those with congenitally absent limbs.

Phantom pain is most commonly thought of as occurring following amputation of a limb but it is also well recognised following amputation of other bodily parts including testis, penis, breast, eye or tongue. The incidence of phantom pain following mastectomy is quoted as high as 15% but is a poorly recognised and seldom acknowledged sequelae of this type of operation.

Phantom pain is usually felt as being located in the distal part of the amputated limb and is often described as being gripping, burning, shooting or cramping in character. Unlike many forms of neuropathic pain, phantom limb pain is commonly intermittent although some patients will experience constant pain. Once established, phantom limb pain can be very resistant to treatment; for instance dense regional anaesthetic blockade provides only limited benefit. Indeed, a number of cases have been reported of patients developing phantom limb pain for the first time while under spinal anaesthetic and also of patients experiencing exacerbations of pre-existing phantom pain with spinal and epidural anaesthesia. This reinforces the view that phantom limb pain is not solely a phenomenon of the peripheral nervous system but involves more widespread and complicated central processes.

Stump pain is common in the early post-operative period. This is an acute nociceptive pain that usually resolves as the wound heals. Stump pain may persist in 5 – 10% of patients due to on-going local pathology or an acute neuropathic process. Sensory examination of the stump at this time may demonstrate hyperalgesia and allodynia. Surgical revision should be avoided if at all possible and is only indicated for localised pathology such as osteomyelitis or abscess. Persistent stump pain may be a risk factor for phantom pain.

At a later stage, once the patient begins rehabilitation and mobilisation, stump pain may develop or be exacerbated due to a poorly fitting prosthesis.

AETIOLOGY OF PHANTOM PAIN

The exact mechanism of phantom limb pain is unknown but it is believed to involve both peripheral and central changes to the nervous system that occur following nerve injury during amputation.

Peripheral mechanisms

Amputation results in the severing of peripheral nerve axons and the formation of neuromas, which are enlarged, disorganised endings of C-fibres and demyelinated A fibres. Neuromas have been shown to demonstrate abnormal spontaneous and evoked activity that is thought to be due to fundamental changes in ion channel function. Altered sodium channel expression has been particularly implicated in this process. There are also changes to dorsal root ganglion cells that display abnormal spontaneous activity and increased sensitivity to mechanical and chemical stimulation. The sympathetic nervous system is also thought to be involved in the pathogenesis and persistence of phantom pain.

Spinal mechanisms

After nerve injury there is an increase in excitability of spinal cord neurons characterised by abnormal spontaneous activity and exaggerated response to mechanical and thermal stimuli. Sensitisation of dorsal horn neurons occurs in response to increased painful stimulus from the amputation site and is mediated by the release of pro-nociceptive agents such as glutamate and neurokinins. This hyperexcitability may result in the clinical picture of mechanical hyperalgesia.

Key to the phenomenon of spinal sensitisation is increased activity in N-methyl D-aspartate (NMDA) receptor mediated systems. These systems are important in the phenomenon of neuronal plasticity whereby the receptive field of a particular neurone is widened by forming new cross-links with adjacent afferent neurones in different laminae within the spinal cord. Other neurotransmitters such as substance P and calcitonin gene-related peptide have also been implicated in this process

Cerebral mechanisms

Soon after amputation there is a reorganisation of primary somatosensory and motor cortices and subcortical structures. Areas of somatosensory cortex which previously corresponded to the missing limb subsequently receive sensory information from other areas of the body that synapse at adjacent areas on the somatosensory cortex. It is thought that phantom pain may be a consequence of errors occurring in this remapping process.

The degree of reorganisation is related to perceived pain intensity and reduces with effective treatment of pain. This can be demonstrated by clinical examination of sensation, which may show a somatotropic representation of the phantom limb on the chest wall, in the stump or on the face.

Many studies have been undertaken investigating methods of preventing phantom limb pain. A popular theory has been the use of pre-emptive analgesia. The constant, supra-normal nociceptive input from an amputated limb is thought to contribute to the neural re-organisation which may lead to phantom pain phenomena. It was hoped that by initiating intensive pre-operative analgesia, particularly by afferent nerve blockade, abnormal neural reorganisation may be prevented. However, in patients who have experienced a period of severe pain pre-operatively these changes may have already taken place.

Much of the early work in this area examined the impact of prolonged pre-operative epidural analgesia on the incidence of phantom pain. Despite showing promising early results, it was later realised that some studies had significant methodological problems and subsequent larger studies found no significant benefit on the overall incidence of phantom pain with this technique. Pre-operative epidural anaesthesia may however decrease the incidence of severe phantom pain but not the overall incidence of phantom pain.

An alternative, and increasingly popular technique to prevent phantom pain involves the placement of peri-neural catheters either pre or intra-operatively. Administration of local anaesthetic at the time of amputation and as a continuous infusion for 72 hrs post operatively has been shown to be of some benefit in helping prevent phantom pain. The addition of clonidine to a peri-neural local anaesthetic infusion may confer an additional benefit.

In common with many areas in pain medicine, there is no strong evidence base to guide treatment of phantom pain. Many studies are of small size with differing end-points and investigate diverse patient groups with different peri-operative anaesthetic management. Consequently, much available evidence is based on small case-series, cohort studies and expert opinion making any firm recommendations difficult. However, some common treatment strategies are detailed below.

Pharmacological

Antidepressants

Tricyclic antidepressants (TCA’s) such as amitriptyline and nortriptyline act by inhibiting the re-uptake of noradrenaline and serotonin thereby potentiating the action of two important central anti-nociceptive pathways. TCA’s have been shown in a number of randomised controlled trials to be effective in the management of a variety of neuropathic pain conditions. Although there are no studies specifically examining the use of TCAs in phantom limb pain, they are commonly used and thought to have modest efficacy. TCAs have a number of side-effects including excessive sedation and anticholinergic side effects such as dry mouth, urinary retention and constipation. These may limit their use. However, when started at low dose, these effects can be minimised.

Duloxetine is a relatively new agent which has shown promise as an analgesic in other types of neuropathic pain (particularly in painful diabetic neuropathy). Duloxetine also acts on serotinergic and noradrenergic pathways similar to TCA’s. Clinical experience with this agent in phantom limb pain is limited; however, one early case report suggests that duloxetine may be beneficial in phantom limb pain.

Serotonin specific re-uptake inhibitors (SSRIs) are less effective in the management of neuropathic pain and consequently are seldom used for this purpose. This lack of efficacy is likely to be a reflection on the much narrower spectrum of action compared to TCA’s.

Sodium channel blockers and anticonvulsants

Gabapentin and pregabalin bind to voltage gated calcium channels and have been shown to be effective in a variety of neuropathic pain problems. Evidence for their use in phantom pain is unclear, with conflicting results from RCTs. Although generally well tolerated, the main dose-limiting side effects of gabapentin are somnolence and dizziness which can be minimised by gradual dose titration.

Second line agents include carbamazepine and lamotrigine. These should be considered after conventional mono and combination therapy with TCA’s and anticonvulsants has failed.

Intravenous lidocaine has been extensively reported as having good efficacy in neuropathic pain and its oral analogue, mexiletine, has also been shown in one small study to produce pain relief in phantom pain. This class of drug can be particularly useful as the analgesic effects are of faster onset in comparison to standard anti-neuropathic agents with the clinical effect often significantly outlasting the pharmacological action of the drug. These agents have a good safety profile and should be considered at an early stage after other first-line agents have been tried.

Tramadol is a synthetically produced drug that has both monoaminergic and opioid activity with less adverse effects than strong opioids. This extended action is particularly useful for neuropathic pain that can involve multiple receptor processes. Tolerance and dependence are uncommon. Tramadol has been shown in a number of studies to reduce neuropathic pain including post-amputation pain.

Other drugs

One double-blind crossover study has shown calcitonin to be effective in treating phantom pain if given early in the post-operative period. This is a clinically well tolerated agent that can be administered as a subcutaneous injection, intravenous infusion or intra-nasal spray. It does not, however, have any proven efficacy in treating established phantom pain.

Intravenous ketamine has been shown to reduce pain, hyperalgesia and ‘wind up’ in those with stump pain and phantom limb pain. However, ketamine administered via the epidural route peri-operatively does not decrease the incidence of phantom limb pain. The use of ketamine is frequently limited by unpleasant neuro-psychiatric side-effects such as hallucinations. An alternative NMDA antagonist is Memantine that has been shown in some small studies to be helpful in managing phantom limb pain if used during the acute or sub-acute phase. This drug has a good pharmacokinetic profile, well suited to pain management, with a better side-effect profile than ketamine.

Non medical treatments

The mirror box is a device containing a vertically placed mirror into which the amputated limb is placed and is positioned so that a reflection of the patient’s intact limb is ‘superimposed’ onto the perceived position of the phantom limb. It has been shown that mirrored movements activate the contralateral sensorimotor cortex, and this is associated with a reduction in pain.

The mirror box is particularly helpful in patients who experience spasms of their phantom upper limb perceived as involuntary clenching of the missing hand. The mirror box allows the patient to visualise the unclenching of this limb which can help relieve the pain of these spasms.

Mental imagery

Alternative methods of stimulating the motor or sensory cortices can also achieve a reduction in phantom limb pain. Mental imagery is the process of imagining motor sequences and is thought to work in a similar way to the mirror box. This follows a program of imagery exercises and can be completed by the patient at home. Studies looking at functional MRI (fMRI) in amputees before and after training in mental imagery have shown a significant reduction in pain which is associated with a corresponding change in cortical MRI signal. This is seen only in patients with amputation pain, and not in amputees with no pain or controls.

Acupuncture and TENS

Other treatments which have been used include acupuncture and TENS. It is not clear where the optimum site for placement of TENS electrodes. One approach is to apply stimulation to the contralateral limb. There may also be benefit in placing electrodes on the chest wall or flank in patients who display clear somatotropic representation of the limb on these areas.

Stump care and prosthetics also have an important role. Immediate fitting of stump prosthesis can be helpful in the management of phantom pain.

Patients may also benefit from explanation and reassurance or therapies such as hypnosis, psychotherapy and cognitive behavioural therapy.

Electrical stimulation

Electrical stimulation of the spinal cord, deep brain structures and motor cortex may relieve pain but its effectiveness may decrease over time. These invasive techniques should be reserved for the most refractory of cases.

Phantom limb pain occurs in 60 – 80% of patients following amputation as result of a combination of peripheral, spinal and cortical changes and is often difficult to treat. Current treatments are predominantly based on evidence from small studies and evidence of benefit in different types of neuropathic pain. Further research is required to examine methods of preventing phantom pain developing and to guide treatment choices in the future.

• Phantom limb sensation, stump pain and phantom limb pain often co-exist
• Phantom limb pain occurs as result of a combination of peripheral, spinal and cortical changes.
• Phantom limb pain is difficult to treat
• Pharmacological therapies include tricyclic antidepressants, sodium channel blockers, anticonvulsants, NMDA antagonists and calcitonin.
• Non-drug treatments such as mirror therapy, acupuncture, TENS, psychology and prosthetics are also important
• Epidural anaesthesia may have a role in preventing phantom limb pain but further studies are required.

ANSWERS TO MCQS

References and further reading.

• Nikolajsen L, Jensen TS. Phantom limb pain. Br. J. Anaesth. 2001; 87 (1): 107-116.
• Nathanson M. Phantom Limbs as reported by S.Weir Mitchell. Neurology 1988; 38:504-505
• Spiegel DR et al. A presumed case of phantom limb pain treated successfully with duloxetine and pregabalin. Gen Hosp Psychiatry . 2010; 32(2):228
• Dworkin RH et al. Pharmacologic management of neuropathic pain: Evidence-based recommendations. Pain 2007; 132 (3): 237-251
• Jaeger H, Maier C. Calcitonin in phantom limb pain: a double‐blind study. Pain 1992; 48: 21–27
• Diers M et al. Mirrored, imagined and executed movements differentially activate sensorimotor cortex in amputees with and without phantom limb pain. Pain 2010; 149: 296-304
• MacIver D, Lloyd M et al. Phantom limb pain, cortical reorganization and the therapeutic effect of mental imagery. Brain 2008; 131 (8): 2181-2191
• Fisher A, Meller Y. Continuous postoperative regional analgesia by nerve sheath block for amputation surgery—a pilot study. Anesth Analg 1991; 72: 300–3
• Churchill Pocketbook of Pain Second Edition 2004 Stannard C, Booth S
• Jackson MA, Simpson KH. Pain after amputation. BJA: Contin Educ Anaesth Crit Care Pain 2004; 4 (1): 20-23.
• Flor H. Phantom-limb pain: characteristics, causes, and treatment. The Lancet 2002 (1); 3:182-189

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Postamputation pain: epidemiology, mechanisms, and treatment

1 Johns Hopkins School of Medicine, Baltimore, MD, USA

Steven P Cohen

2 Johns Hopkins School of Medicine and Uniformed Services, University of the Health Sciences, Bethesda, MD, USA

Postamputation pain (PAP) is highly prevalent after limb amputation but remains an extremely challenging pain condition to treat. A large part of its intractability stems from the myriad pathophysiological mechanisms. A state-of-art understanding of the pathophysiologic basis underlying postamputation phenomena can be broadly categorized in terms of supraspinal, spinal, and peripheral mechanisms. Supraspinal mechanisms involve somatosensory cortical reorganization of the area representing the deafferentated limb and are predominant in phantom limb pain and phantom sensations. Spinal reorganization in the dorsal horn occurs after deafferentataion from a peripheral nerve injury. Peripherally, axonal nerve damage initiates inflammation, regenerative sprouting, and increased “ectopic” afferent input which is thought by many to be the predominant mechanism involved in residual limb pain or neuroma pain, but may also contribute to phantom phenomena. To optimize treatment outcomes, therapy should be individually tailored and mechanism based. Treatment modalities include injection therapy, pharmacotherapy, complementary and alternative therapy, surgical therapy, and interventions aimed at prevention. Unfortunately, there is a lack of high quality clinical trials to support most of these treatments. Most of the randomized controlled trials in PAP have evaluated medications, with a trend for short-term Efficacy noted for ketamine and opioids. Evidence for peripheral injection therapy with botulinum toxin and pulsed radiofrequency for residual limb pain is limited to very small trials and case series. Mirror therapy is a safe and cost-effective alternative treatment modality for PAP. Neuromodulation using implanted motor cortex stimulation has shown a trend toward effectiveness for refractory phantom limb pain, though the evidence is largely anecdotal. Studies that aim to prevent PA P using epidural and perineural catheters have yielded inconsistent results, though there may be some benefit for epidural prevention when the infusions are started more than 24 hours preoperatively and compared with nonoptimized alternatives. Further investigation into the mechanisms responsible for and the factors associated with the development of PAP is needed to provide an evidence-based foundation to guide current and future treatment approaches.

Historical aspects

The word amputation can trace its origin to the Latin term “amputatio,” meaning “to cut around.” Yet, amputations have been practiced since the dawn of mankind. Historical and archaeological records demonstrate that purposeful amputations have been performed since Neolithic times, dating back at least 45,000 years. 1 This evidence consists of stone knives and saws found with the skeletal remains of amputated stumps.

It is likely that postamputation pain (PAP) has plagued humans for countless millennia. However, our understanding of PAP has significantly evolved over the centuries, with the full impact beginning to unravel only recently. Perhaps the major advances in amputation care and our understanding of their sequelae have occurred during war. For hundreds of years, horrific limb injuries have been the result of man’s fascination with armed conflict. Reporting on 86 civil war amputees, the renowned physician Weir Mitchell coined the term “phantom pain,” recording an incidence as high as 90%. 2

But for the most part, the concept of PAP was largely ignored by the mainstream medical establishment, with post-World War II prevalence rates consistently estimated at less than 5%. 3 , 4 Moreover, many of these patients were ostracized, and their symptoms attributed to either psychopathology or secondary gain. 4

Today, the management of amputations engenders public attention and research dollars far in excess of its epidemiological burden. PAP is widely considered to be one of the most challenging among all pain conditions to treat, as is evidenced by the plethora of trials that continue to be conducted. A large part of its intractability stems from the myriad pathophysiological mechanisms that can result in PAP. Whereas mechanism-based pain treatment is generally considered to be superior to etiologic-based therapy, 5 , 6 the obstacles involved in identifying the predominant mechanism(s) – which are prodigious under the best of circumstances – can become nearly insurmountable for a condition as phenotypically and pathogenetically disparate as PAP. The purpose of this review is therefore to provide an evidence-based framework from which to evaluate therapies and guide treatment for PAP.

Definitions and epidemiology

In the United States, the prevalence of limb loss was 1.6 million in 2005, which is projected to increase to 3.6 million by 2050. 7 Approximately 185,000 upper- or lower-limb amputations are performed annually. According to a study by Dillingham and colleagues examining data from the Healthcare Cost and Utilization Project from 1988 to 1996, vascular pathology is the most common etiology, accounting for 82% of limb loss discharges followed, in descending order, by trauma (16.4%), cancer (0.9%), and congenital anomalies (0.8%). 8 The loss of a body part can lead to painful and nonpainful neurologic sequelae that fall into three distinct descriptive categories: phantom limb pain (PLP), residual limb pain (RLP), and phantom sensations (PSs). Although these categories will be described independently, one cross-sectional study by Ephraim and colleagues performed in 914 individuals with limb loss found that up to 95% experienced at least one of these categories. 9 Furthermore, patients surveyed about their postamputation sensations often have a difficult time distinguishing one category from another. 10

PLP is a painful or unpleasant sensation in the distribution of the lost or deafferentated body part. PLP varies in character from neuropathic-type descriptors such as sharp, shooting, or electrical-like, to more nociceptive-specific adjectives such as dull, squeezing, and cramping. It can be localized to the entire limb or just one region of the missing limb. PLP typically occurs within the first 6 months after loss of a limb, but its prevalence several years after surgery has been reported to be as high as 85%, and it can persist for years after surgical amputation. 11 , 12 In a prospective study evaluating 58 patients who underwent limb amputation, Jensen et al found that PLP changed over time from an exteroceptive-like pain (ie, knife-like or sticking) localized to the entire limb or a proximal region, to a more proprioceptive-like pain (burning or squeezing) localized to the distal areas of the amputated limb. 13

PLP should be distinguished from RLP, also known as “stump” pain, which is localized to the remaining body part after amputation. Stump pain is typically described as a sharp, burning, electrical-like, or “skin-sensitive” pain which can be localized to a superficial incision, be perceived deep in the residual limb, or sometimes encompass the whole residual limb. The reported incidence of stump pain can be as high as 74%, and similar to phantom pain can persist for years. 14 Stump pain can be further subdivided into postsurgical nociceptive, neurogenic, prosthogenic, arthrogenic, ischemic, sympathetically maintained, pain referred from the spine or joints, or pain secondary to abnormal stump tissue such as adhesive scar tissue or heterotopic ossification. 12 Although PLP and RLP often coexist, RLP is usually more bothersome immediately after amputation, whereas PLP may predominate 1–12 months after the amputation event. 15 Studies have found a significant correlation between the magnitude of RLP and PLP. 16

PSs are defined as nonpainful perceptions emanating from the lost body part after deafferentation or amputation. PSs are common in the postoperative period, with one-third of patients experiencing PSs within 24 hours, three-quarters of patients within 4 days, and 90% of patients within 6 months after surgery. 13 Unlike PLP and RLP, amputation of a body part is not essential prior to the development of PSs. PSs have been reported after avulsion of the brachial plexus without amputation of the limb, 17 and following spinal cord injury. 18 PSs can be subdivided into kinetic, kinesthetic, and exteroceptive perceptions. Kinetic sensations are perceived movements of the amputated body part that can be willed or spontaneous, such as the movement of toes in an amputated foot. Kinesthetic sensations refer to the size, shape or position of the amputated body part, such as feeling that a hand is twisted. Exteroceptive perceptions can include touch, pressure, tingling, temperature, itch, and vibratory sensations. 18 PSs are typically experienced in regions with disproportionately large cortical representation, such as the hands and feet. PSs can result not just from amputation of an extremity but also excision of other body parts such as the breast after mastectomy, which is estimated to occur in approximately 25% of individuals. 19 Telescoping refers to the perception of progressive shortening of the amputated limb, which results in the sensation that the distal part of the limb is becoming more proximal. 13 For example, a patient with an above the elbow amputation may initially feel phantom pain or sensations in the entire forearm and hand. Over time, the same patient may perceive his or her hand to be close to the stump, but not feel the proximal forearm. This phenomenon occurs in one-quarter to two-thirds of major limb amputees. 20

PAP is primarily a clinical diagnosis based on history and physical examination, though certain tests can help rule out alternative and often remediable diagnoses such as referred back pain, residual ischemia, prosthesis-related pain, neuromas, pressure-related wounds, and infection. A study by Smith and colleagues performed in 92 patients undergoing amputation found that back pain was more prevalent (71%) compared with that of the general population (45%). 21 Patients with chronic mechanical lower-back pain may have referred pain to the leg from such sources as the lumbar zygapophysial and sacroiliac joints, which can be mistaken for PLP. 22 Ischemic injury must be ruled out in patients presenting with PAP, especially since a large proportion of patients who undergo amputation have vascular insufficiency as the underlying etiology. Tests of distal perfusion such as transcutaneous oxygen tension (positive for ischemia if less than 20 mmHg) at the level of the residual limb can be useful in ruling out an ischemic etiology. Diagnosing a neuroma as a source of RLP may be useful when formulating a treatment plan. A positive Tinel’s sign (tapping on the injured nerve or neuroma elicits pain in the phantom limb or stump) represents a classic feature for neuroma. Prosthesis-related pain is often mistaken for classical RLP or PLP, and in some cases can be easily remedied. Occasionally, residual limbs may atrophy over time leading to stump shape changes relative to the original mold obtained during the casting process. This results in load-bearing and other forces inside the socket to shift from weight-tolerant to intolerant areas, which can cause erosion of the skin around contact points and overlying bony tissue. A careful skin and soft tissue examination of the stump can effectively rule out pressure wounds or frank infections that may be developing. Pressure points that develop over bone spurs or pathologic bone formation (ie, heterotopic ossification) can be a source of localized pain, which can be identified on plain radiographs. Infections such as osteomyelitis and residual graft infection can also be a source of chronic PAP.

Although primarily used in pain research, quantitative sensory testing (QST) may be a valuable tool for the diagnosis and management of PAP. QST entails the determination of pain thresholds or stimulus response curves for sensory processing under normal and pathophysiological conditions. For example, QST has been used to provide quantitative objective measures of neuropathic pain via the conductance of thermal testing in regions of heat allodynia, which can improve diagnosis and inform treatment. 23 – 27 In short, QST may allow clinicians to better phenotype patients, which in turn may improve treatment outcomes.

Treatment of PAP is very challenging because the underlying mechanisms are multifactorial in nature. Since mechanisticbased pain treatment is generally acknowledged to be superior to etiologic-based treatment, the difficulty in identifying a discrete mechanism(s) which can be directly addressed results in corresponding barriers to treatment. 5 The pathophysiology underlying phantom phenomena can be broadly categorized in terms of supraspinal, spinal, and peripheral mechanisms (see Figure 1 ). Supraspinal mechanisms related to phantom limb phenomena primarily involve reorganization of the somatosensory cortex surrounding the area representing the deafferentated limb. Ramachandran and colleagues demonstrated that brushing the face of upper limb amputees could elicit PSs. 28 They hypothesized that somatosensory cortical reorganization could explain why afferent nociceptive stimulation of a body part (eg, proximal stump or face for upperlimb amputees) whose cortical representation is adjacent to that of the phantom can produce sensations in the phantom. Specifically, tactile, proprioceptive, and nociceptive input from the face and tissues near the residual limb take over regions of the brain that no longer receive afferent input. Functional magnetic resonance imaging (MRI) studies after amputation of the hand have demonstrated that the cortical area corresponding to the hand is activated during proximal limb movements, and that cortical stimulation of this region evokes contraction of proximal upper-limb muscles. 29 – 32 The greater the size of the deafferentated area and extent of cortical reorganization, the more intense the PSs. 33 , 34

Mechanism-based treatment modalities for postamputation pain.

Abbreviation: NMDA, N-methyl-D-aspartate.

The evidence for peripheral mechanisms playing a role in PAP include the demonstration of spontaneous neuronal activity in the proximal end of cut nerves, the presence of stump pathology in some patients with phantom pain and the strong correlation between RLP and PLP, and the relief of phantom pain after the injection of local anesthetic into the painful stump. 13 , 35 Axonal nerve damage during an amputation initiates inflammation and regenerative sprouting which results in a neuroma. Afferent fibers in the neuroma develop ectopic activity, mechanical sensitivity, and chemosensitivity to catecholamines. Altered expression of transduction molecules, upregulation of voltage-sensitive sodium channels, downregulation of potassium channels, and the development of new nonfunctional connections between axons (ephapses) all serve to increase spontaneous afferent input to the spinal cord. 36 These changes may lead to spontaneous pain, and help explain the amplification in pain caused by emotional distress and/or exposure to cold that leads to increased sympathetic discharge and circulating catecholamines. 20

The spinal mechanisms for PAP are thought to center on functional changes in the dorsal horn of the spinal cord after deafferentation from a peripheral nerve injury. The loss of afferent input to the dorsal horn leads to decreased impulses from brainstem reticular areas, which normally exert inhibitory effects on sensory transmission. 37 Therefore the absence of inhibitory effects for sensory input arising from the missing peripheral body part cause increased autonomous activity of dorsal horn neurons, in effect becoming “sensory epileptic discharges.” 11 , 12 The contribution of spinal cord mechanisms is illustrated by the fact that anticonvulsants, and lesions placed in the substantia gelatinosa, are effective in treating phantom pain. 38 Similar to cortical reorganization, a “spinal reorganization” process has also been described in which adjacent afferent fibers “invade” regions of the spinal cord that are functionally inactivated by injured afferent fibers. 38 Clinically, the evidence supporting spinal mechanisms is bolstered by: the development of phantom pain in lower-extremity amputees following new lumbar disc herniations, and new-onset phantom pain in an amputated upper extremity associated with herpes zoster infection, both of which have been successfully treated with epidural steroid injections; 39 the evocation of phantom pain with spinal analgesia; 40 and an unusual case in which longstanding PLP disappeared with the development of cauda equina compression by a tumor and recurred following decompression. 41

Multiple cellular, neurochemical and molecular changes underlie the peripheral and central reorganization phenomena that occur in the postamputation period. Studies of nonhuman primates have demonstrated that chronic deafferentation can cause distal axon sprouting and the formation of neuromas, 42 chromatolysis (dissolution of Nissl bodies in the neuronal cell body) and loss and fibrosis of dorsal root ganglion cells, 43 – 46 atrophy or degeneration of central terminations of sensory neurons in the brainstem 46 and spinal dorsal horn, 45 , 47 sprouting of sensory neuron terminations in the dorsal horn, 48 , 49 decreased myelination, and changes in neuropeptide levels in dorsal root ganglia and the dorsal horn. 50 In the first month after amputation, nerve injury can cause transsynaptic atrophy of central neurons. Neurochemically, lower-limb amputations lead to decreased lectin binding and substance P levels and upregulated neuropeptide Y. 51 , 52 These peripheral neuronal changes have been observed from about 2 months to as many as 38 years after amputation, and appear to be concurrent with changes in the brainstem. Immunohistochemical studies evaluating changes in the dorsal column nuclei of chronic upper- and lower-limb amputees have revealed some atrophy of cuneate and gracile nuclei ipsilateral to the amputation, as well as proliferation of astrocytes, reactive gliosis, and inflamed axons (spheroids). 53 These findings suggest that amputation triggers neurochemical/molecular changes that cause degenerative and regenerative changes in primary sensory axons in the dorsal column nuclei.

Ultimately, pain after amputation is likely caused by a combination of the above mechanisms as total spinal anesthesia, cordotomy, cordectomy, spinal cord stimulation, and regional anesthesia of the plexus or stump have at best yielded only modest relief of phantom pain. As noted above, in some cases spinal anesthesia can even rekindle phantom pain that previously subsided. 54 , 55 Hence, the interactions between peripheral, spinal, and supraspinal phenomena are all thought to contribute to postamputation phenomena, and should all be considered when planning treatment.

Injection therapy

There are few controlled trials available to guide pain practitioners in the optimal management of PAP, with most therapies extrapolated based on effectiveness in other neuropathic pain states. Presently, the state-of-the-art treatment of PAP involves a multimodal approach that includes injections, pharmacotherapy, complementary and alternative therapies, surgery, and prevention.

Based on available evidence, local injection therapy appears to be more efficacious in the treatment of RLP compared with PLP. This appears to be due to the greater contribution of peripheral mechanisms in RLP compared with PLP. Although regional nerve blocks using lidocaine and/or corticosteroid often results in immediate relief of RLP, the duration of pain relief is highly variable and temporary. 56 , 57 An active area of research aims to prolong this effect. One small randomized controlled pilot study examined the Efficacy of focal chemo-denervation using perineural injection of botulinum toxin type A compared with combination lidocaine and depomedrol. The study found that while both therapies showed a trend toward Efficacy, botulinum toxin resulted in a statistically significant improvement in RLP at 1 month, which was sustained over the 6-month study period. Neither modality improved PLP. 58 Another small series found a similar short-term benefit for RLP with the local injection of botulinum toxin B. 59 A separate small case series found that for patients who experienced relief from a diagnostic lidocaine injection, pulsed radiofrequency was effective in relieving RLP, although the effects were mixed for PLP. 60 Another small case series found perineural injection of the tumor necrosis factor inhibitor to be effective in patients with PLP and RLP of less than one year duration and tender points on physical examination. 61 A small observational study demonstrated that sympathetic dysfunction may play a role in the pathogenesis of PAP, and that sympathetic nerve blocks may provide some short-term relief of PLP, and to a lesser extent RLP. 62 It is important to note that local injection therapy may have effects beyond providing local peripheral blockade of pain input. One small observational study found that contralateral myofascial injection with local anesthetic in unilateral amputees attenuated PLP and PSs in the affected limb, though follow-up was limited to 1 hour. 63 Whereas the precise mechanism for this effect is unclear, animal studies have demonstrated that blocking afferent inputs on the contralateral side can decrease spontaneous hyperactivity of wide dynamic response neurons on the injured side, suggesting that a spinal mechanism may be at work. 64

Pharmacotherapy

When choosing pharmacotherapy for patients with established PAP, the practitioner must consider chronicity, route of administration, and adverse effects. There are six groups of medications for which there is evidence in the treatment of PAP: N-methyl-D-aspartate (NMDA) receptor antagonists, opioids, anticonvulsants, antidepressants, local anesthetics, and calcitonin (see Table 1 ).

Randomized controlled trials of pharmacologic interventions for the treatment of postamputation pain

Notes: a “+” designates studies that show a statistically significant improvement of the study drug over placebo in the treatment of postamputation pain, and “ −“ designates studies that do not

Abbreviations: IV, intravenous; NMDA, N-methyl-D-aspartate.

NMDA receptor antagonists including ketamine, dextromethorphan, and memantine are thought to block a cascade of events leading to sensitization of dorsal horn wide dynamic range neurons. In patients with PLP or RLP, Nikolajsen and colleagues found a significant decrease in pain intensity, wind-up-like-pain, and pressure-pain thresholds following a 45-minute low-dose ketamine infusion compared with a normal saline control. 65 Although most of the participants in this study had PAP following amputations for cancer, a more recent study by Eichenberger found 1 hour ketamine (0.4 mg/kg) and ketamine plus calcitonin infusions to be effective for up to 48 hours compared with placebo for participants with various etiologies of PLP. No benefit was noted for calcitonin either alone or combined with ketamine. 66 Likewise, oral dextromethorphan has been shown to be effective in reducing pain intensity in a small placebo-controlled crossover study comprised of patients with PLP, 67 but oral memantine has not been shown to have analgesic properties when treating patients with established PLP. 68 – 70 Interestingly, memantine has been efficacious in combination with brachial plexus blockade to prevent PLP acutely, suggesting that the timing of administration may be important. 71 Whereas the evidence for ketamine is strongest, the short follow-up periods and high incidence of adverse effects, including alterations in consciousness, visual hallucinations, hearing impairment and mood changes, limit its long-term usefulness.

Opioids may be beneficial in the treatment of PAP due to its mechanism of action at both the spinal level, where it inhibits pain signaling pathways, and supraspinal level, where it may diminish the degree of cortical reorganization associated with pain intensity. 72 Both oral and intravenous opioids administered for up to 6 weeks have been shown to be effective for PAP. 72 – 74 In fact, Huse and colleagues showed that cortical reorganization was reduced in two of three participants with PLP undergoing treatment with oral morphine at both 6 and 12 months follow-up for one patient, and during the treatment phase for the other. 72 Similarly, tramadol has been shown to be effective in treatment of long-standing PAP compared with placebo over a 1-month treatment period. 75 Among the two opioid class medications, morphine has the more severe adverse-event profile, which includes constipation, sedation, tiredness, dizziness, sweating, voiding difficulty, vertigo, itching, and respiratory problems.

Anticonvulsants have long been a mainstay in the treatment of neuropathic pain. However, studies examining gabapentin as a treatment for established PAP have been conflicting with both positive and negative trial results. 76 , 77 Gabapentin was associated with significant side effects in both studies, including somnolence, dizziness, headache, and nausea.

Calcitonin has a direct central action which causes inhibition of neuronal firing in response to peripheral stimulation. 78 This mechanism of action has encouraged interest in calcitonin as an adjunctive medication in the treatment of PAP. However, studies to date have been variable. One early controlled crossover study by Jaeger and Maier demonstrated a reduction in pain intensity compared with placebo that was sustained through 1-year follow-up in 8 of 13 patients with postoperative PLP who received a single calcitonin infusion. 79 However, a more recent study by Eichenberger et al evaluating calcitonin as a treatment for established PLP found calcitonin to be ineffective compared with placebo, attributing its ineffectiveness to a possible lack of effect on central sensitization processes. 66 Adverse effects of calcitonin included headache, vertigo, drowsiness, nausea, emesis, and hot/cold flashes.

Sodium channel blockers have been shown to be effective for both neuropathic and inflammatory pain. One study assessing amitriptyline in the treatment of PLP or RLP did not show a significant difference compared with placebo after 6 weeks of treatment, although patients in the treatment group did experience adverse effects such as dry mouth and dizziness severe enough to cause dropouts. 80 Whereas tricyclic antidepressants act in part via the blockade of sodium channels, their main mechanisms of action involve enhancement of descending inhibitory pathways via the inhibition of serotonin and norepinephrine reuptake. Similarly, evidence for using primary sodium channel blocking medications has been mixed at best. One double-blind study by Wu et al found that whereas intravenous morphine provided significant immediate-term relief of both PLP and RLP compared with placebo, intravenous lidocaine alleviated only RLP. 73 In a placebo-controlled follow-up study by the same group in 60 patients with PAP, morphine but not the oral lidocaine analogue mexiletine provided significant pain relief at 6-week follow-up. 74

Complementary and alternative therapies

The refractory nature of PAP to traditional medical and interventional therapies underscores the importance of developing complementary and alternative therapies. Psychological interventions for PAP aim to facilitate adaptation to pain, body image, and negative emotions associated with amputation. In one randomized controlled trial of 20 patients with 6 months of RLP or PLP, hypnosis administered in three individual sessions reduced overall pain scores when compared with pre-intervention scores. 81 Evidence for other psychological techniques such as guided imagery (creating mental images that help promote relaxation and healing) and biofeedback (learned control over autonomic physiologic processes) is mostly anecdotal. 82 , 83 In one case series by Beaumont et al in which six amputees with chronic PLP underwent visual-kinesthetic feedback therapy over 8 weeks, four participants demonstrated greater than 30% reduction of pain after the intervention but only one maintained this over 6 months of follow-up. The authors pointed out that psychological health, social support, and the degree of control prior to the intervention may be significant factors in determining those who benefit compared with those who do not. 82

Cognitive behavioral therapy (CBT) has been used successfully in patients with chronic neuropathic pain conditions. 84 – 86 In particular, a case series by Tichelaar and colleagues involving three patients with complex regional pain syndrome type I suggested that CBT may address pain mediated by central cortical reorganization. 86 Although there are no controlled trials showing Efficacy for CBT in PAP, there is an ongoing randomized controlled trial by McQuaid and colleagues designed to test whether CBT plus mirror therapy is superior to supportive care in amputees. 87 Whereas psychological interventions such as hypnosis, biofeedback, guided imagery, and CBT are safe and minimally invasive, large-scale trials are lacking and there is little evidence for long-term benefit.

Mirror therapy exploits the brain’s predilection to prioritize visual information over somatosensory feedback and is believed to treat PAP by influencing cortical reorganization. Flor et al showed that the degree of phantom pain correlates with the degree of maladaptive reorganization of somatosensory pathways using functional MRI, and that reorganization can be reversed by mirror therapy with a corresponding reduction in pain. 88 , 89 Also known as visual mirror feedback, mirror therapy involves placing a mirror adjacent to the intact limb to give the illusion that the amputated limb is present and can be purposefully moved. Since it was introduced in 1992 by Ramachandran and Altschuler, 90 multiple studies have demonstrated short-term pain reduction using visual feedback using both mirrors and virtual reality or video modalities. 91 , 92 Chan et al randomly assigned six patients each to one of three groups, mirror therapy, covered mirror therapy, and trained visual imagery, and showed that after 4 weeks, pain decreased in the mirror therapy group, stayed the same in the covered mirror therapy group, and increased in the visual imagery group. Nine of the patients in the covered mirror and visual imagery groups crossed over to the mirror therapy group, with a mean decrease in pain of 75% over the next 4 weeks compared with their baselines. 93 Because sensory experiences can be evoked by visual stimuli, mirror therapy increases spinal motor and cortical excitability. 94 The simplicity and noninvasiveness of this treatment modality has led to its application not only following limb loss, but also for the prevention of PAP. 95

Surgical therapies

Although surgical interventions have not demonstrated significant benefit in well designed trials, patients with chronic intractable PAP who fail the aforementioned treatment modalities may sometimes be considered for surgical management. 12 Surgical modalities fall into two general categories: neuromodulatory techniques and reconstructive. Neuromodulatory therapies are by definition mechanism driven, targeting maladaptive neuroplastic changes at the peripheral, spinal, and supraspinal levels. Although there are no randomized controlled trials to demonstrate Efficacy and safety for peripheral nerve stimulation (PNS), PNS has the potential to be especially effective in patients for whom the majority of pain is confined to the distribution of one or two peripheral nerves. Historically, peripherally placed electrodes required surgical dissection of the nerve in order to place the electrodes along the nerve trunk. 96 Recently, Rauck and colleagues demonstrated that a PNS lead inserted percutaneously and remotely from the target nerve in a single patient with RLP could lead to both pain relief and improvement in quality of life outcomes at 2 weeks follow-up. 97 The emergence of percutaneous techniques may change the risk/ benefit for patients with refractory RLP, and represents a promising area of future study. Whereas targeting peripheral mechanisms may be sufficient in patients with RLP, those with central sensitization or deafferentation, as occur with PLP, require neuromodulation at spinal or supraspinal levels. Spinal cord stimulation has been shown to be effective in a number of neuropathic pain states, but the evidence for its Efficacy in PAP is less robust, with several studies demonstrating inferior outcomes compared with peripheral neuropathic pain. 98 – 102 The evidence that does exist is mainly limited to small case series that report “successful outcome,” with the criteria for a successful outcome varying drastically between studies 98 – 104 (see Table 2 ). Nonetheless, spinal cord stimulation is reimbursed by Medicare specifically “to treat intractable pain caused by phantom limb syndrome that has not responded to medical management.” 105 Although still considered investigational by the Food and Drug Administration, motor cortex stimulation in PAP is very promising. One meta-analysis of 155 patients from nine studies of motor cortex stimulation in various chronic pain states show that 53% of patients with PLP were treated successfully, with follow-up periods that ranged from 6 months to 10 years. 106 Motor cortex stimulation directly targets the site of cortical reorganization and pain by using precise positioning techniques such as preoperative functional MRI and awake intraoperative stimulation. Deep brain stimulation has been shown to be more effective in nociceptive pain conditions such as failed back surgery syndrome rather than in deafferentation central pain states, and is associated with mixed results in patients with PA P. 107

Studies evaluating neuromodulation for the treatment of postamputation pain

Abbreviations: DBS, deep brain stimulator; MCS, motor cortex stimulator; PNS, peripheral nerve stimulator; SCS, spinal cord stimulator; VAS, Visual Analog Scale.

The contribution of peripheral mechanisms is greater in RLP compared with PLP; therefore, surgical reconstruction can be successful in treating RLP associated with distinct pathologic lesions. For example, heterotopic ossification is highly prevalent in patients with traumatic amputation, with a prevalence rate of up to 63%. 115 In the same study by Potter and colleagues, 20 of 25 patients with traumatic amputations whose heterotopic ossifications were excised were able to discontinue or reduce their opioid and/or neuropathic pain medication consumption at an average of 12 months follow-up. 115 Neuromas are an inevitable sequelae of major nerve injury or transaction, and clinically significant neuromas may occur in up to 80% of cases, presenting as a discrete area of pain and abnormal sensation in the distribution of a single peripheral nerve. 116 Frequently, a Tinel’s sign can be elicited. Whereas this typically manifests as pain in the residual limb, referred pain from the stump into the phantom limb can also occur. Unlike with heterotopic ossifications, the long-term outcomes of peripheral nerve surgery are mixed. Several older studies have reported only a short duration of pain relief, with recurrence of the neuromas and RLP redeveloping months after initial resection. 117 – 119 Nonetheless, more recent retrospective and prospective studies have shown that peripheral nerve reconstructive techniques could lead to improvement in pain and quality of life for both RLP 120 and PLP. 121 Currently, peripheral nerve reconstruction remains a viable option for RLP refractory to interventional and pharmacologic treatment modalities.

In view of the inherent challenges and limited success observed in treating PAP, many investigators have attempted to find ways to preemptively treat acute PAP, thereby preventing acute PAP from becoming chronic. For the purpose of this review, preemptive interventions shall refer to interventions which take place preoperatively, intraoperatively, or in the early postoperative period (<2 weeks) after an amputation, with the goal being to avert long-term spinal sensitization by blocking nociceptive input after peripheral nerve injury. 122 In general, the evidence supporting preemptive interventions to reduce or prevent chronic pain have been limited to small trials of varying quality. A systematic review by Halbert et al identified eight controlled trials in which a preemptive intervention, including epidural treatments (three trials), regional nerve blocks (three trials), intravenous calcitonin infusion (one trial), and transcutaneous electrical nerve stimulation (TENS; one trial) was used to prevent or treat acute PLP. 123 The results were mixed for epidural treatments, with one small trial showing decreased PLP at 1 week, 6 months, and 1 year follow-up, another small trial showing decreased PLP which only reached statistical significance at 6 months follow-up, and the largest, most methodologically sound trial showing no difference between the two groups. 124 – 126 The trials for peripheral nerve blocks, calcitonin, and TENS all showed no difference in pain control between intervention and control groups in long-term follow-up (6 months or greater). 127 – 130 The authors also used a quality assessment instrument to determine the likelihood of bias in three areas: randomization, double-blinding, and withdrawals or dropouts. 131 In their discussion, they note that the reviewed trials were of poor overall quality due to the use of a variety of PLP outcome measures, which prevented examination of the treatment effect on pain. Overall, they concluded that the evidence does not support treatment of acute PLP in the acute postoperative period. 123

Treatment strategies for preventing the development of chronic postsurgical PAP primarily focus on blocking nociception at the spinal and peripheral nerve levels. The area that has been best studied is the use of epidural anesthesia for prevention of PAP. As summarized in Table 3 , the evidence overall has been conflicting, with several promising early studies suggesting that preoperative epidural anesthesia could decrease incidence of PLP. 124 , 125 , 132 However, more recent studies have been mixed at best, with several showing no effect. 126 , 133 , 134 One recent study by Karanikolas et al showed that optimized epidural or systemic analgesia started 48 hours preoperatively was similarly effective in reducing the incidence of PLP at 6 months. 135 Overall, these studies suggest that timing may be critical; compared with studies that demonstrate no benefit for preemptive epidural analgesia, those that demonstrate effectiveness were more likely to implement treatment 24 hours or more preoperatively 124 , 125 , 135 (see Table 3 ). Another important factor affecting study results seems to be the effectiveness of the “control” treatment, as those studies in which the nonepidural or control treatment group was carefully managed have been less likely to demonstrate a benefit than those in which postoperative pain care was suboptimal. 134 – 136

Prospective studies evaluating epidural effect on preventing phantom limb pain

Notes: a Randomization and blinding of study participants and investigators was either employed “+” as a method in the study or not employed “–”;

Abbreviations: IM, intramuscular; IV, intravenous; PCA, patient-controlled analgesia.

For perineural anesthesia, the available evidence is limited to several studies whose results are conflicting. An uncontrolled study by Borghi et al (n = 71) 137 showed that continuous peripheral nerve blockade that starts immediately preoperatively or intraoperatively and continues postoperatively can be effective in reducing the incidence of severe PLP, with the benefit persisting for up to 12 months. A randomized, controlled study that compared continuous postoperative brachial plexus block with the oral NMDA receptor antagonist memantine to brachial plexus blockade alone found that that the addition of memantine reduces the incidence of PLP at 4 weeks and 6 months, but not at 12 months. 71 However, a small (n = 21) randomized, controlled study by Pinzur et al found that sciatic nerve blockade begun immediately postoperatively fails to prevent phantom pain compared with a control group that received saline, though it did decrease postoperative opioid consumption. 130 Collectively, these studies do not support the routine use of postoperative perineural anesthesia to prevent PLP, though the effect of preoperative nerve blockade warrants further investigation.

Systemic therapies have demonstrated mixed results in preventing PAP. A small placebo-controlled crossover study done in the early 1990s (n = 21) evaluating intravenous calcitonin early in the postoperative period found a reduction in lower extremity PLP for up to 24 hours that persisted in an open-label phase for most patients throughout their 1-year follow-up. 79 Yet, a larger and more methodologically sound study comparing gabapentin – a first-line medication for neuropathic pain 138 – with placebo starting on postoperative day 1 and continued over a 30-day period failed to show any benefit during the 6-month follow-up period. 139

Several studies have examined the effects of complementary and alternative treatments in preventing PAP. A randomized, controlled study conducted in 51 patients with acute lower extremity amputations compared TENS with sham TENS plus chlorpromazine, and sham TENS alone, for the prevention of PLP, re-operation rates, and postoperative wound healing. 140 Although a lower incidence of PLP occurred at 4 months in the active TENS group, no differences were observed at 4 weeks or 1-year post- amputation. Of note, the active TENS group experienced more rapid stump healing and a lower re-amputation rate than the control groups. Despite the recognition of the importance of supraspinal mechanisms in the treatment of existing chronic PAP, few studies have been performed evaluating the utilization of supraspinal modalities for the prevention of PAP. In a four-patient case series by Hanling and colleagues evaluating 2-weeks of preemptive mirror therapy prior to elective limb amputation, one patient did not experience PLP, two patients reported rare episodes of mild PLP, and one patient had moderate PLP, for up to 1-month post-surgery. 95 This suggests that preventative strategies targeting supraspinal mechanisms such as mirror therapy, may be a promising area for future research.

Conclusion and future directions

PAP remains a highly prevalent but difficult-to-treat condition for patients undergoing amputations. Treatment must be multimodal and mechanism-based in nature, taking into consideration supraspinal, spinal, and peripheral mechanisms. Further investigation into the mechanisms responsible for and the factors associated with the development of PAP is needed to provide an evidence-based foundation to guide current and future treatment approaches. The authors believe that the following developments have the potential to provide additional tools to the pain practitioner.

Because there are different mechanisms involved in PAP, a systematic method for classifying patients is needed. Based on current understanding of the disorder, a phenotypic model may be helpful. For example, classifying patients by diagnostic category (ie, RLP versus PLP), referral patterns, descriptors, associated signs and symptoms, as well as chronicity may help determine which mechanisms predominate and guide therapy. These phenotype therapies would not necessarily be multimodal since they would be individualized to each patient’s predominant pain mechanism. Future studies could be designed to elucidate how phenotypic groups respond to different mechanism-specific therapies.

Controlled studies exploring multimodal treatments and preventative measures may also be on the horizon. Gilron and colleagues have described similar studies for the use of preemptive multimodal analgesics in the perioperative period for patients undergoing abdominal hysterectomy. 141

Monoclonal antibody-based therapeutics have revolutionized the treatment of oncologic and inflammatory disorders, and hold promise in the treatment of chronic pain. 142 For patients with PAP, antibody-based treatments could offer safer and more effective alternatives to currently available treatments. In addition to tumor necrosis factor alpha inhibitors, antibodies against several other pain-specific targets are currently under development. For example, anti–nerve growth factor antibodies have demonstrated Efficacy in the treatment of pain in patients with osteoarthritis and chronic low back pain. 143 , 144 This may herald the advent of a new class of medications for the treatment of PAP.

Finally, though phenotypic classification of patients may be more applicable in the near term, preclinical studies have shown that a portion of individual variability in pain thresholds and susceptibility can be explained by differences (or mutations) in genotypes and gene expression. 145 , 146 Costigan et al identified one single nucleotide polymorphism within KCNS1 , the gene encoding a voltage-gated potassium channel, which is constitutively expressed in sensory neurons downregulated following nerve injury. 147 In this study, six different cohorts of chronic pain patients to include two separate groups of lumbosacral radiculopathy subjects, women with post-mastectomy pain, PAP, and PLP, along with a control group of healthy adults, were tested for experimental pain. Collectively, these patients showed a significant increase in self-reported pain that was associated with a specific single nucleotide polymorphism of KCNS1 . Further genotypic studies of this nature may help to identify individuals at higher risk for developing neuropathic pain after amputation who need aggressive early pain management to prevent the development of PAP.

The authors did not receive any grants, consulting fees, honorariums, support for travel, or costs associated with writing or editing this manuscript.

The week's good news: Oct. 19, 2023

It wasn't all bad!

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West Virginia high schoolers band together to keep the music going

Students design the world's first off-road solar-powered suv, new ai tool could be a game changer for surgeons, innovative prosthesis could help amputees dealing with phantom limb pain, chicago marathon runner rescues kitten during the race.

The Pocahontas County High School Band has just 10 members, but a whole lot of heart. This West Virginia school is in a rural area, and when the band director left and the principal couldn't find a replacement, students were given two options: sign up for another class during fifth period or teach themselves. Drummer Hailey Fitzgerald told The Washington Post she was motivated to keep the band going because "we played together for years — we're like a family." Ten kids chose to stay with the band, with some even picking up new instruments so there weren't so many drummers, and Fitzgerald was named director. At the first football game of the year, fans in the stands held up signs for the band, and alumni came out for Homecoming to join in a performance. "To see so many people supporting and cheering us on, that's a huge motivator," clarinetist Jadyn Lane said. "That's when you know all the hard work is worth it." The Washington Post

A team of 22 students at Eindhoven University of Technology in the Netherlands have developed the Stella Terra, billed as "the world's first off-road solar-powered vehicle." The SUV's sloped roof is outfitted with solar panels that charge the electric battery, which is smaller than traditional electrical vehicle batteries. In early October, the students tested the vehicle in Morocco, due to its "huge variety of landscapes and different surfaces in quite a short distance," Thieme Bosman, the team's events manager, told CNN. They drove 620 miles from Tangier to the Sahara Desert, and found the SUV was more efficient than expected. When it's sunny, the battery has a range of 411 miles on roads and 342 miles off road. The goal is to create a vehicle that can get deliveries and aid to areas "where roads are less developed and energy grids are not as reliable," Bosman said. CNN

Surgeons may soon have a new tool that could help them decide how aggressively to operate on patients with brain tumors. It can be difficult to determine how much healthy tissue should be removed around a tumor, and if not enough is extracted, cancerous cells could be left behind. In a study published last week in the journal Nature, researchers from the Netherlands wrote that they used artificial intelligence to develop a method called Sturgeon, which involves "a computer scanning segments of a tumor's DNA and alighting on certain chemical modifications that can yield a detailed diagnosis of the type and even subtype of the brain tumor," The New York Times explained. Because this uses a faster genetic sequencing technique, doctors could learn more about the tumors while at the operating table, helping guide their surgical decisions. During the first test of 50 frozen tumor samples, 45 were accurately diagnosed within 40 minutes, while five were unclear. A second test involving live brain surgeries had 18 correct diagnoses in less than 90 minutes, with five unclear.  The New York Times

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A first-of-its-kind bionic prosthesis has proved "life-changing" for a Swedish engineer named Karin. Twenty years ago, Karin lost her arm below the elbow in a farm equipment accident. She did not use a prosthesis until now, when she was fitted with an arm using "osseointegration," a process where bone tissue and titanium come together "creating a strong mechanical bond and enabling connection with the nervous system" through electrodes in the nerves and muscles, Good News Network reported. This prosthetic was designed by researchers in Australia, Italy and Sweden, and Karin said now that it's attached to her, she no longer has phantom limb pain. She first underwent surgery for the bionic arm in 2018, and her physician, Dr. Ortiz Catalán, said the fact she's been able to use the prosthesis comfortably for several years "is a promising testament to the potential life-changing capabilities of this novel technology for individuals facing limb loss." Good News Network

Sarah Bohan was on mile 21 of the Chicago Marathon last week when she saw out of the corner of her eye a kitten under a pile of leaves. Bohan was on track to setting a personal record, but she was also running on Team PAWS Chicago to benefit the animal welfare organization, and knew she couldn't leave the cat behind. She asked multiple people along the course if they'd take him, and after a mile, she met the kitten's match, Andrea Maldonado. Her family has two cats and a dog already, Maldonado told Insider, but she welcomed the new addition because "the more the merrier." The kitten, now named Casper, received a clean bill of health and has settled right in with the Maldonados. Insider

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Catherine Garcia is night editor for TheWeek.com . Her writing and reporting has appeared in Entertainment Weekly and EW.com , The New York Times , The Book of Jezebel , and other publications. A Southern California native, Catherine is a graduate of the University of Redlands and the Columbia University Graduate School of Journalism.

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