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Pathophysiology and management of phantom limb pain
Clinical Problems in Psychiatric Treatment of the Medically Ill Effective psychiatric intervention with the medically ill requires adapting the techniques of psychiatric diagnosis, psychotherapy, and psychopharmacology to each specific medical illness. This section, edited by Barry S. Fogel, M.D. and Alan Stoudemire, M.D., will address diagnostic technologies, special topics in clinical psychopharmacology, and special applications of psychotherapy appropriate to patients with concurrent medical and psychiatric disorders. Articles will review and examine the literature on these topics to derive guidelines for clinical practice.
Pathophysiology and Management of Phantom Limb Pain David D. Harwood, M.D., Sai Hanumanthu, Alan Stoudemire, M.D.
Abstract: Phantom pain phenomenon is a poorly understood but relatively common sequela of limb amputation that may result in significant psychological and physical morbidity. ln this review, proposed pathoneurophysiological mechanisms for the development of phantom pain are reviewed as well as psychological mechanisms that may be involved. The authors recommend an integated approach to management of chronic phantom pain that takes into consideration the multiple factors that may contribute to its etiology.
Introduction Phantom limb pain is a frequent sequela of amputation [l-4]. Estimates on the number of surgical and traumatic amputations of both major (limbs) and minor (digits) extremities from 1981 to 1987 show approximately 230,000 surgical amputations per year and an average prevalence of injuries resulting in amputation of 6.0/1000 persons per year, or a total of 1.3 million traumatic amputations per year [l]. Recent amputee surveys estimate that From the Department of Psychiatry, Air University (AU) Regional Hospital, Maxwell Air Force Base, Montgomery, Alabama (DDM, SH); and the Medical-Psychiatry Unit, Emory University Hospital and Emory University School of Medicine, Atlanta, Georgia (AS). Address reprint requests to: Alan Stoudemire, M.D., Emory Clinic-5th Floor, Psychiatry, 1365 Clifton Road, N.E., Atlanta GA 30322. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of Defense or the US Government. Generd Hospital Psychiatry 14, 107-118, 1992 0 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
B.A., and
60%-80% of all limb amputees experience phantom pain [l-3]. In a 1984 survey [5] of chronic phantom and stump pain among American veterans, it was found that the majority (35%) of amputees who reported phantom limb pain indicated that they were hindered by pain for 2-5 days per month. Twenty-seven percent mentioned a period of greater than 20 pain days per month [1,2]. Although phantom pain phenomena have attracted the interest of scientific investigators from many disciplines, there has been a striking lack of systematic studies of this subject [1,2]. The purportedly “indelicate” nature of the subject matter may have led Dr. S. Weir Mitchell in 1866 to report his observations of phantom limb pain anonymously, in a lay periodical [6]. The current literature on phantom limb phenomena is sparse and contradictory, reflecting only partial understanding of underlying mechanisms. Most clinical reports are based mostly on short-term studies with small groups [1,2]. It is important to note that the term “phantom pain” subsumes several distinct pain sensations. Mechanisms thought to influence one type of phantom pain may or may not be involved in a different type of sensation. Insufficient attention to subtyping the painful sensations in the medical literature has contributed to the unsatisfactory nature of attempts to explain the entire phenomenon of phantom pain. In order to clarify discussion of phantom pain
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symptoms, Ribbers et al. [2]. have suggested the following definitions: Phantom: The continuous awareness of a (or part of a) nonexisting or deafferented body part with specific form, weight, or range of motion. Phantom Sensation: Each nonpainful sensation of the phantom. Phantom Pain: Each painful sensation felt in the stump (e.g., pain due to neuromata, exostoses, postoiera&e pain, and pain caused by abnorma1 sensitivity termed allodynia [2]. This article will review the current literature describing the psychological and physiological factors thought to be relevant in phantom pain, as well as discuss treatment strategies that have been recommended for its management.
Literature Review First reported by Ambrose Pare in 1551 [2], descriptions of phantom pain have been largely consistent among most amputees. Typical painful feelings include 1) shooting/shocking, 2) cramping, 3) stabbing, 4) burning, and 5) squeezing [l]. A central feature is a “tingling feeling and a definite shape that resembles the somatosensory experience of the real limb before amputation” [4]. There is also growing evidence of phantom phenomena in amputated parts other than limbs. Kroner, et al., described a 25.8% incidence of “phantom breast syndrome” among 120 women following mastectomy [7]. Reported by 70% of amputees in the first few weeks after amputation, phantom limb pain persists in approximately 50% even 7 years after amputation [4]. Several theories have been proposed to account for this phenomenon. It has been suggested that preoperative limb pain plays a role in phantom pain immediately after amputation, but probably not in late persistent phantom pain. In a prospective study of 58 patients undergoing limb amputation, it was found that during the first six months after limb loss phantom pain was significantly more frequent in patients with long-lasting preamputation limb pain and in patients with pain in the limb immediately prior to amputation than in patients without preoperative pain. Phantom pain and preamputation pain were similar in both localization and character in 36% of patients immediately after amputation but in only 10% of patients at six months’ followup [8]. 108
Kroner et al. found similar results in a prospective study of 120 women undergoing mastectomy. The authors, based on their findings, postulated that “constant painful sensory input prior to amputation established a long-lasting sensory engram in the brain’ [7].
Neurophysiological Mechanisms Based on earlier work with Loeser on paraplegics, Melzack [4] proposed a neurophysiological theory involving the concept of a neuromatrix, defined as “a network of neurons that extends throughout widespread areas of the brain, composing the anatomical substrate of the physical self.” Melzack suggested that the neuromatrix, which subserves body sensation, has a “genetically determined substrate that is modified by sensory experience.” According to this explanation, “loss of modulating input from limb or body causes the neuromatrix to produce an abnormal signature pattern created by the patterns that flow through the neuromatrix.” The result of the insult on the signature pattern is that it “subserves the physiological qualities of heat or burning-the most common qualities of phantom limb pain.” This neuromatrix is thought to be genetically determined, as even children born without limbs have occasional phantom phenomena . The neuromatrix is not structurally confined to the “somatosensory cortex,” as excision of this brain structure does not prevent the eventual reappearance of phantom sensations, including pain. Melzack [4,9] suggested that the neuromatrix comprises a complex interplay of neural systems, or “substrate of the physical self,” including thalamocortical, limbic, and occipital components. The concept as presented is elegant in that emphasis is shared between peripheral and central mechanisms. Melzack cautions against attributing exclusive explanatory value of peripheral neurovascular mechanisms in pain perception; that is, despite the vaguely defined nature of neuromatrix, sensory ingrams, morphogenetic fields, and so forth, it is certain that the brain and its subsystems are critical in centrally modulating input. As Figure 1 indicates, a host of other theoretical mechanisms have been offered to explain the development of phantom phenomena. It is useful to sort them by their purported anatomical foci relating to 1) the periphery, 2) the spinal cord, 3) the autonomic nervous system, and 4) changes up to
Phantom
MECHANISMS THEORETICALLY INVOLVED IN PHANTOM LIMB PAIN
5,6
-1,2,3,4 Figure 1. Proposed sites for the neuropathophysiology of phantom limb syndrome. Key: 1) Neuroma information; 2) Vascular changes; 3) Pressure receptor changes; 4) Local chemical changes; 5) Degenerative changes at spinal and supra spinal levels; 6) Microvascular changes in spinal cord blood supply; 7) The “Neuromatrix”
the level of the spinal cord (central
PI.
mechanisms)
Advocating the predominant role of a peripheral mechanism in the etiology of phantom limb pain, Jensen et al. [lo] and Ribbers et al. [2] reported that manipulation of the stump influences phantom pain. Wall [ll] and Ribbers et al. [2], in earlier experimentation in animals immediately postamputation, revealed multiple nerves sprouting at the stump end, resulting in abnormal and erratic local It was proposed that newly depolarizations. formed nerve bulbs in recovering tissue are more sensitive to the locally elevated levels of tissuerelated growth and pain-modulating factors leaking into the immediate environment due to the damaged blood-nerve barrier [2,11]. This presumed that an increase in the sprouting of small cutaneous nerves in the skin flaps might be a causal
Pain Pathophysiology
and Management
factor in the short-term postoperative development of burning or cramping pain (probably from chaotic large-muscle activity by aberrant local nerve input) 12,111. Skepticism exists, however, on how much importance should be attributed to peripheral mechanisms. An alternative explanation to the findings of Jensen et al. [S] is in terms of “altered afferent input into a central system” [2]. Further, phantom sensation in cases of spinal anesthesia (where there is no nerve damage or regenerative sprouting) demonstrates that peripheral mechanisms may not necessarily play a major causal role in this type of phantom pain development [2]. Evidence from the model of local anesthesia (which can result in phantom sensations other than pain) provides indirect support for the role of spinal cord mechanisms in the pathogenesis of phantom pain [2,11]. Ribbers et al. [2] offer the example of an apparently swollen cheek after dental anesthesia. Because anesthesia makes depolarization impossible, and the time of phantom onset is not sufficient for any known chemical substance to traverse the area of the block to the spinal cord, the pain was believed to be the result of disinhibition of active spinal cord neurons. Distinct changes at the level of the spinal cord after section of a peripheral nerve have been reported by Wall as “immediate” and u11 and characterized “chronic” changes. Immediate changes involve an increased excitation of partly afferent cells due to disinhibition and the regeneration of receptive fields in cells. The chronic pattern involves changes in metabolism, along with chemical and morphological changes in the afferent terminals of the spinal cord. After 10 days, changes in cellular peptide concentration within the dorsal horn imply that “the effect of the peripheral nerve lesion has spread beyond the damaged cells into the spinal cord mechanism itself” [2,11]. An alternative pathway thought to influence phantom pain involves autonomic nervous system fibers, which are primarily linked to blood vessels (including small capillaries and larger arteries) that completely bypass the spinal cord. As proposed by Lawrence [12], these fibers would transport pain impulses directly to higher structures of the central nervous system [2]. Evidence cited to support this theory is based on the observation that relief of pain (thought to be secondary to long-term changes in blood flow) accompanies perivascular sympathectomy. Modulation of the perivascular fibers, then, should also influence phantom pain if such 109
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a connection does indeed exist. In paraplegics, for example, the stimulation of the perisosteum of the vertebrae, an area richly innervated by sympathetic fibers and linked above and below the level of transection by blood vessels “eliminated phantom pain for varying periods of time” [2,12]. It is unlikely, however, that disinhibited autonomic neurons are the primary cause of phantom pain. As has been observed, “If phantom pain could be explained in terms of disinhibited spinal cord neurons, it should be possible to provoke it by local anesthesia. Such a phenomenon has not yet been described” [2]. In other words, phantom sensations do not necessarily lead to the development of phantom pain. A “central” explanation is proposed by Katz and Melzack [13] who report that referred sensations (paresthesias, pain, temperature changes, pressure, or constriction) were experienced in a sample of 98 chronic pain patients during electrical stimulation applied at the outer ears, face, and torso. This theory proposes that somatosensory input from the area of electrical stimulation targets excitatory neuron pools in the central nervous system, resulting in “multiple sensations that are perceived to originate in the periphery.” “Deafferentation due to disease, injury, or lesions of the central nervous system lead to a hypersensitivity and an increased likelihood of referred pain of long duration” [ 131. Further evidence of a central mechanism arises from observations of transneural changes up to the level of the thalamic nuclei following deafferentation, and the observation that the nature of chronic pain is similar to thalamic pain syndrome and anesthesia dolorosa [ 14,151. The specific neurophysiological systems involved in referred pain phenomena require substantial elucidation at the basic science level, but the models presented above are clearly the most persuasive examples available for a tentative understanding of the various phantom pains.
for different people, depending on such factors as the sex, age, and occupation of the individual. For example, amputation may have greater significance for the elderly because “it seems to symbolize the encroachment of death.” As Caplan and Hackett [16] observed, “the fact that a part of {him} has died and been destroyed makes all too vivid the stark realization that the rest of the body is equally vulnerable and disposable.” The loss may thus be overtly manifest as fear over the apparent imminence of death, imparting sadness in the life, job, family, and social interactions of the individual. Parkes [2,17,18]. viewed the grief associated with the loss of limb as part of the mourning syndrome: “Just as the widow finds it hard to believe that her husband is dead and often has a strong sense of his presence, so the amputee has difficulty in accepting the loss of his limb and he continues to feel that it is present.” Mitcherlich [19] considered the phantoms to be “the result of a conflict between the archaic present desire for regeneration and the definite acceptance of the loss of the amputated limb” [16]. Frazier and Kolb [20] proposed three psychological factors thought to be most important in the etiology of phantom pain: “unresolved fantasies about the amputated limb, previous association with an amputee, which was frequently morbid, and overemphasis on bodily parts.” There have been no correlations in the literature between “heavily emphasized body parts” and the frequency of phantom pain. Other authors believed that people with “rigid’ and “compulsive selfreliance” profiles on psychological testing seem to have more persistent pain [20]. In an analysis of the literature on psychological factors influencing phantom limb pain, Sherman [21] concluded that chronic phantom limb pain is “magnified” by stress, anxiety, and depression, but there is no evidence to suggest an increased incidence of anxiety or depressive-spectrum disorders in amputees with phantom pain.
Psychological Aspects
Reported Treatments of Phantom Limb Pain
In addition to neurophysiological explanations of phantom pain, the psychological aspects of limb loss have been explored from many perspectives. The psychodynamics of limb loss seem most useful clinically as a means of understanding the patient’s total experience, and notably less helpful when
Sherman [21] identified 43 individual treatments purporting to successfully treat phantom limb pain. The following discussion highlights several treatment strategies (Table 1). It should be noted, however, that most of these reports, several of which will be outlined below, consist of small numbers of patients in open treatment trials without placebo controls.
they imply causality in specific physiological sensations. The loss of a limb has different meanings
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Excellent anesthetic with no trace of PLP until the block began to wear off. Pain was more severe and in a different site than the usual phantom. “Heel pain” ceased within 5 minutes of completion of the infusion. Only two fleeting episodes occurred over the next 12 hours. They were left untreated and mild nausea was reported. TENS is initially effective for phantom pain. No difference between placebo and actual treatment groups after 1 year. No differences in pain until after 4 months following treatment when phantom pain prevalence was significantly lower with active TENS treatment. No complications related to the technique were observed.
Case report, n = 1. Epidural anesthesia for C-section. Total dose of 26 ml of 0.5% bupivacaine given in increments over a 1 hour period. Case study, n = 1. 100 IU salmon calcitonin was given intravenously over 5 minutes.
Placebo controlled, n = 51. Long-term follow-up of TENS. Unblinded. Fifty-one patients were randomized: SHAM TENS and chlorpromazine. SHAM TENS (control). Low frequency TENS-active (more rapid stump healing).
Controlled pilot study, II = 11. Retrospective control goup. Continuous regional analgesia by nerve sheath block for lower limb amputation. Continuous infusion of 0.25% bupivacaine at 10 ml/hour for 72 hours. Demanded 1.4 mg of morphine compared to 18.4 mg for the control.
Carrie et al
Fiddler et al
Finsen et al
Fisher et al
Author At 1 year, three of controls had phantom pain, none of the blockaded patients did.
(PLP).
Controlled randomized trial, n = 25. Performed lumbar epidural blockades before amputations on 11 of 25 elderly patients. Unblinded.
limb pain
Bach et al
for uhantom Outcome
treatments MethodlTechniaue
Table 1. Selected
Follow-up of the group for up to 12 months showed total absence of pain despite the presence of preoperative limb pain.
Clinical experience suggests TENS is still a good way to disrupt a chronic pain pattern.
Follow-up over several months showed a return to baseline PL status. Calcitonin may act via serotonergic mechanisms to increase the activity of descending pain suppressing systems and thereby inhibit transmission of PLP.
Epidural anesthesia did not produce phantom pain during its period of action as reported under spinal anethesia.
Reducing preoperative pain thought to result in the difference.
Comment
Intravenous subanesthetic dose of thiopental should be tried immediately when I’LP occurs during spinal anesthesia.
Nine patients responded immediately and noted a clear analgesic effect.
Pain was completely short term.
Thirty years of persistent phantom pain abated completely. Side effect; patient had diminished ability to calculate. Successful short-term with propranolol.
Controlled study, n = 10. Immediate response of phantom limb pain to calcitonin after a single injection. Patients with persistent or acute PLP. Case study, n = 3. Intravenous subanesthetic doses of thiopental in several patients with previous lower limb amputations. Case study, n = 1. Persistent PLP. Dramatic response to chlorpromazine in 56-year-old female. Case study, n = 3. Treatment for burning phantom pain; Bblockers.
Kessel and Worz
Koyama et al
Logan, T.
Marsland
et al
et al
Jacobson
treatment
abolished
Fast reaction, within 5-30 minutes. Optimal dosage is yet to be determined. Lasted from 2 hours to 3 months. Side effects.
Fentanyl always abolished pain. Median analgesia duration for 8 hours. Lidocaine relieved discomfort but did not abolish the pain.
Case study, n = 8. Comparison of 25 pg lumbar intrathecal fentanyl and 70 pg lidocaine 2 weeks apart.
et al
Jacobson
Supports the claim of a vascularrelated mechanism for burning phantom pain.
Authors conclude the case points to a central mechanism of pain.
Primary importance is given to a central mechanism involving the spinal cord in the modulation of established stump pain in the eight subjects.
Neuraxial. Intrathecal and epidural fentanyl produced its good effects by segmental spinal action. Spinal modulation was important to postamputation pain.
Temporarily abolished the pain, normalized sensations. Produced euphoria without supraspinal efects.
Case study, n =2. Intrathecal fentanyl 25 pg to postamp PLP and stump pain patients, respectively. Intrathecal fentanyl at various doses on one patient.
Comment
Outcome
Author
Method/Technique
Table 1 (continued)
5
W
Urban, B. J. et al Consecutive case, 12 = 5. Uncontrolled. Used methadone and doxepin in variable doses (methadone 1520 mg daily; doxepin 25-150 mg daily).
Case study, n = 16. Biofeedback.
et al
Sherman
Case study, n = 1. Carbamazepine in the treatment of PLP.
Case study, II = 22. All underwent Dorsal Root Entry Zone (DREZ). Six months to 4 years followup.
J. F.
Saris et al
Patterson,
Greater than 50% improvement in pain control in all five patients at 22 months.
Biofeedback training designed to reduce muscle tension led to long-term reduction or disappearance of phantom pain.
Eight of 22 had pain relief, 6 of 9 PLP patients had relief, and 5 of 6 with traumatic amputations associated with root avulsion had relief. Poor results for patients with both stump and PLP or stump alone.
As the carbamazepine level approached therapeutic levels, the patient became less concerned with his pain, though it was still present. When treatment stopped, pain returned.
No problems with abuse/ tolerance of narcotics. All patients had failed previous treatment regimens.
General correlation between intensity of cramping phantom pain and intensity of muscle tension. Conclude that chronic phantom pain is affected by stress, anxiety, and depression.
DREZ procedure has a welldefined but limited role in postamputation treatment.
Experience to date indicates the need for controlled doubleblind crossover studies to test therapeutic validity.
D. D. Harwood et al.
Parenteral and spinal injection strategies. Calcitonin represents a novel approach for phantom limb treatment. Following a single intravenous injection of 100 IU of calcitonin to 10 patients with persistent or acute phantom limb pain, nine patients responded immediately with diminished pain. A control group of nonphantom pain patients did not respond at all, except for one patient with chronic stump pain. Within 5-30 minutes, relief of pain was noticed; the therapeutic effect was attributed to activation of a central inhibitory system. The optimal dose of calcitonin is still open, given significant side effects of dysesthesia, nausea, and vomiting [ZZ] . In a randomized, prospective trial in which lumbar epidural blockades were performed prior to amputations on 11 of 25 patients, at 1 year, none of the 11 blockade patients and 3 of the 14 controls had phantom pain. In this study, 11 patients were given active epidural blockades and 14 were given sham treatment. The difference was attributed to reduced preoperative pain in the active group [23]. In an uncontrolled series of two patients with postamputation stump and phantom limb pain, Jacobson et al. [24] reported that intrathecal fentanyl was able to transiently abolish the painful sensations without producing supraspinal effects. The authors also found that intravenous fentanyl and intravenous lidocaine were unable to reproduce the anesthetic effects derived from intrathecal administration. They suggest that segmental spinal action with spinal modulation of postamputation pain was responsible for the differential response, and that this demonstrates the predominant role of spinal vs peripheral mechanisms in the etiology of phantom limb pain. In another case report involving an amputee with “severe and intractable acute postamputation phantom foot pain,” Jacobson and Chabal [25] were able to “extinguish established phantom limb pain and restore normal sensations for about 8 hours.” Prior to an intrathecal injection of fentanyl, a number of pain treatments (morphine, meperidine with hydroxyzine, patient-controlled intravenous analgesia with morphine, and oxycodone with acetaminophen) proved ineffective. Following the single dosage of intrathecal fentanyl 25 mg, epidural morphine (5 mg) therapy was injected every 12 hours via the epidural catheter for 11 days, during which time there was no recurrence of phantom pain. Given the fact that significant changes take place in spinal cord areas dense with opiate receptors following peripheral nerve tran114
section, opioids may “offer the potential for effective treatment and prophylaxis of postamputation pain” [25]. In a comparative, single-blinded, controlled study reporting the effectiveness of intrathecal lidocaine and fentanyl on established postamputation stump pain, Jacobson et al. [26] administered lumbar intrathecal fentany125 mg and lidocaine 70 mg 2 weeks apart to eight patients with established lower limb postamputation stump pain. In contrast to intrathecal lidocaine which served only to relieve the discomfort, intrathecal fentanyl was able to “abolish” the pain such that analgesia was complete by 5-10 minutes following administration and lasted a median of 8 hours. With lidocaine, the median duration of analgesia was 2 hours, and pain was not abolished in three of eight patients. In accordance with earlier studies, the authors suggested that intrathecal fentanyl provided analgesia via a segmental spinal action, and that “through its action on spinal opioid receptors, subarachnoid fentanyl altered the impulse pattern signaling pain in a way that was perceived as pleasant.” This study once again redirects attention from peripheral mechanisms to central mechanisms involving the spinal cord and to the potential importance of spinal opioids in further elucidation and therapy of postamputation stump pain [26].
Oral pharmacological strategies. Short-term success for burning phantom pain has been achieved with beta-adrenergic blocking agents, particularly strongly lipophilic agents like propran0101.The improvement reported with beta-blockers implies support for the claim of a vascular-related mechanism for burning phantom pain, with implications for use of sympathetic blocks and sympathectomy to increase blood flow to the limbs [27]. Carbamazepine and chlorpromazine have had good therapeutic results. In a case reported by Patterson [28], as carbamazepine levels approached therapeutic levels, the patient became less concerned with his pain, although it was still present. At blood levels of 4 ng/ml, pain was present but not readily noticed. At 10 ng/ml, pain was totally ablated. When treatment was stopped, pain returned. In a single-case report, a 56-year-old female who was suffering from 30 years of persistent, severe phantom pain became free of pain after treatment with chlorpromazine [29]. The use of anticonvulsants and neuroleptics in phantom limb pain is unsubstantiated by formal studies but sug-
Phantom Pain Pathophysiology and Management
gested by inference from the literature on neuropathic and other chronic pain states. When Urban et al. [30] treated five consecutive patients with “intractable” phantom limb pain with methadone 15-20 mgld and doxepin 25-100 mgld, a greater than 50% reduction in pain was demonstrated, which was maintained over the course of 2 years. No associated problems (tolerance, abuse) were noted from the narcotic use [30]. Other treatments. Freed [31] recently presented a review of acupuncture treatment for phantom pain, relating the purported effectiveness to a bodachieved with acupuncture. This ily “stillness” stillness was thought to be related to 1) alpha rhythm prominence on electroencephalogram, 2) deep general relaxation, 3) an increased pain threshold, and 4) total body involvement. This idea requires empirical testing before it can be critically addressed. Transcutaneous electrical nerve stimulation (TENS) has been reported to be initially effective for phantom pain. In a study involving 51 patients who had undergone major amputation of the lower limb, Finsen et al. [32]. reported that “the prevalence of phantom pain after active TENS was significantly lower after 4 months but not after more than 1 year” [33]. In an uncontrolled study designed to reduce muscle tension in 16 phantom limb patients, biofeedback training led to long-term reduction or disappearance of phantom pain in 14 of the 16 patients. A general correlation was observed between the intensity of cramping phantom pain and the intensity of muscle tension [34]. Neurosurgery. Iacono et al. [35] recently reviewed surgical treatments available for phantom limb pain. A broad range of treatments have been employed including stump revision, neuroma resection, cordotomy, mesencephalotomy, and dorsal rhizotomy, none of which were recommended. Surgical options possibly effective after exhausting all available nonsurgical modalities include 1) direct peripheral nerve stimulation, 2) spinal cord stimulation, 3) deep brain stimulation, and 4) spinal dorsal root entry zone lesion (DREZ). Surgical procedures such as thalamic surgery, cordotomy, sympathectomy, nerve strangulation above the stump end, and surgery at the stump have received mostly negative reviews. There are few details on procedures to alter physically interpretive centers of the brain. The few successes
that are reported are confined to case studies with minimal follow-up [21]. Savis et al. [36], in an uncontrolled series of 22 patients with postamputation stump pain and phantom limb pain treated with DREZ, found 36% (8/22) had significant pain relief at follow-up from 6 months to 4 years. It was noted that 67% (6/9) of patients with phantom pain alone experienced significant improvement, whereas none of the six patients with stump pain alone experienced improvement. This implies central and peripheral origins for phantom and stump pain, respectively, and suggests that peripheral nerve stimulation may be useful for stump pain management. Deep brain stimulation, chiefly of the thalamus, periventricular gray, and internal capsule produced significant improvement in 86% of a population of 30 patients with intractable phantom pain ]371. Invasive spinal cord stimulation was studied in an uncontrolled fashion with 64 patients, 52% of whom reported good results at 2-year follow-up, with much less improvement noted for stump pain J381. As this catalog of treatments suggests, successful rehabilitation is dependent upon medical, social, psychological, and vocational factors, and no single factor judged independently guarantees a meaningful rehabilitation.
Discussion To illustrate a practical approach to the management of phantom limb pain, a typical case from our practice illustrates the management of phantom pain that did not require invasive anesthetic techniques.
Case Hishy Ms. J, a healthy 27-year-old, received multiple injuries in a motor vehicle accident, including a traumatic below-the-knee (BRA) amputation of her right leg. One month postinjury we were consulted to assist in pain management. The patient was experiencing persistent frequent “electricity-like” pain in her right stump, “lower leg,” and “foot,” as well as episodic “crushing” pain in the stump and calf area. She was also found to have developed a concomitant depressive disorder. When her pains had been unimproved by trials of several nonsteroidal agents, low-dose narcotics, and TENS, as well as homeopathic doses of amitrip115
D. r>. HaMroodet al.
tyline, Ms. J was begun on doxepin, which was titrated over several days to 150 mg/day. Regular schedules of a potent oral narcotic, hydromorphone 2-4 mg every 4 hours, and ibuprofen 800 mg every 8 hours, replaced the oxycodone/acetaminophen she had been receiving p.r.n. The patient, family, and staff were educated about phantom pain and physical therapy (including massage, graded exercise, and hydrotherapy) before it was initiated. The pain relief was rapid, particularly the crushing pain. The depressive symptoms resolved over several weeks, and 6 months postoperatively she was tapered off the narcotic without recurrence of pain. She was seen weekly throughout this time frame in supportive psychotherapy where education, family involvement, and exploration of the meaning(s) of her loss of body integrity/function were prominent features. As illustrated in the above case, our approach to the treatment of phantom pain employs multiple interventions from several disciplines. As our patient felt “suspect” in her complaints and the ward staff was becoming impatient with her progress, education assumed a primary role in reducing the tension. Through discussion of the complex nature of phantom pain, the patient experienced a dramatic reduction in the “vague notion” that she was psychologically unstable. A strictly “medical” (e.g., neurophysiological) model of phantom pain was presented, and the initial recommendation was vigorous, scheduled treatment with a potent narcotic known to the staff as a medication for “serious” pain. Medication p.r.n. was discontinued because it seemed to result in undermedication and increased frustration for both the patient and the staff. The patient’s positive symptom relief reinforced this approach. Full psychiatric evaluation revealed a concomitant mood disorder which was treated in an aggressive standard manner. The course of treatment showed that reducing the symptoms of the mood disorder correlated in time with decreased pain (vs lowered sensitivity). Physical therapy was immediately involved for the future-oriented tasks of vigorous rehabilitation and eventual prosthetic use. Finally, joint sessions with the patient and her husband were utilized to support their adaptation and anticipate potential problem areas. One possible explanation for the successful outcome in our example case was doxepin’s presumed ability to “reregulate” a dysregulated amine-
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mediated system (the paleospinothalamic tract, PSTT) that produced both pain and disordered mood [39-411. In addition, tricyclic antidepressants, including doxepin, may directly relieve pain by altering brain levels of biogenic amines, specifically serotonin and norepinephrine, which are thought to modulate pain perception and sensitivity [42]. Doxepin may also enhance the bioavailability of both naturally occurring endorphins and enkephalins and opiate analgesics by direct binding to opiate receptors in the brain [42,43]. This may explain the maintenance of pain relief when the hydromorphone was discontinued. The patient herself assumed a more psychological explanation: she felt that as her depression resolved she was more able to tolerate the residual phantom pain, had more capacity to distract herself, and became less inclined to be preoccupied with pain. The nature of the association, if any, between chronic pain and depression is unclear and controversial [44]. Ward, et al. [393 have suggested that certain types of pain (chiefly tonic, dull, burning and poorly localized sensations) are mediated by the PSTT which may be affected by the same imbalance of biogenic amines thought to be involved in the onset of depression [39]. This is the type of pain typically associated with phantom phenomena.
Summary The difficulties in formulating a comprehensive explanation for phantom pain with subsequent generation of testable hypotheses regarding treatment may be one of definition. As alluded to earlier, our suspicion is that there are several types of phantom pain, mediated differently with different causal contributions and different responses to treatment. It is clear that phantom pain is a clinical event wellsuited to the “biopsychosocial” model, with fundamental neurophysiological events manifesting themselves in multiple areas of the patient’s life. Further, individual treatment modalities of all types, from psychoanalysis to aggressive neurosurgical procedures, have had predictably unsuccessful outcomes. The literature, as reviewed here, reveals a paucity of both basic research and clear clinical guidelines for the treatment of patients with phantom pain. Given the significant incidence of this problem and the uniformly poor interventions to date (beyond the isolated case report), further research into the specific brain events mediating
Phantom
carefully delineated types of painful sensations is needed.
References 1. Sherman RA: Stump and phantom limb pain, Neurol Clin 7:249-264, 1989 2. Ribbers G, Mulder, Rijken R: The phantom phenomenon: a critical review. Int J Rehab Res 12:175-186, 1989 RA, Sherman CJ: Prevalence and charac3. Sherman teristics of chronic phantom limb pain among American veterans. Am J Phys Med 62:227-238, 1983 4. Melzack R: Phantom limbs and the concept of a neuromatrix. Trends Neurosci 13:88-92, 1990 5. Sherman RA, Sherman CJ, Parker L: Chronic phantom and stump pain among American veterans: results of a survey. Pain 18:83-95, 1984 M: Phantom limbs are reported by S. 6. Nathanson Weir Mitchell. Neurology 38:504-505, 1988 HS: Long-term 7. Kroner K, Krebs B, Skov J, Jorgensen phantom breast syndrome after mastectomy: incidence, clinical characteristics and relationships to premastectomy breast pain. Pain 36:327-334, 1989 I’: Im8. Jensen TS, Krebs B, Nelson J, Rasmussen mediate and long-term phantom limb pain in amputees: clinical characteristics incidence, and relationships to pre-amputation limb pain. Pain 21:267-278, 1985 body pain in para9. Melzack R, Loeser JD: Phantom plegics: evidence for a central pattern-generating mechanism for pain. Pain 4:195-210, 1978 10. Jensen TS, Krebs B, Nielsen J, et al.: Phantom limb, phantom pain and stump pain in amputees during the first 6 months following limb amputation. Pain 17:243-256, 1983 with am11. Wall I’D: On the origin of pain associated putation. In Siegfried J, Zimmermann M (eds), Phantom and Stump Pain. Berlin, Springer, 1981 RM: Phantom pain: a new hypothesis. 12. Lawrence Med Hypotheses 6:245-248, 1980 sensations in chronic 13. Katz J, Melzack R: Referred pain patients. Pain 28:51-59, 1987 S: Nerves and Nerve Injuries. Edin14. Sunderland burgh, Churchill-Livingstone, 1978 T, Otsuka M: Regional distribution of 15. Takahasaki substance P in the spinal cord and nerve roots of the cat and the effect of root section. Brain Res 87:1-11, 1975 effects of lower 16. Caplan LM, Hackett TP: Emotional limb amputation in the aged. N Engl J Med 269:11661171, 1963 studies of grief in adult 17. Parkes CM: Bereavement: life. London, Tavistock, 1972 the persistence of 18. Parkes CM: Factors determining phantom pain in the amputee. J Psychosom Res 17: 97-108, 1973 A: Das phantomglieb, seine Deutung 19. Mitcherlich und Bedeutung. Schweiz Med Wochenschr 77:423425, 1947
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20. Frazier SH, Kolb LC: Psychiatric aspects of pain and the phantom limb. Orthop Clin North Am 1:481495, 1970 21. Sherman RA: Special review: published treatments of phantom limb pain. Am J Phys Med 59232-241, 1980 22. Kessel C, Worz R: Immediate response of phantom limb pain to calcitonin. Pain 30:79-87, 1987 23. Bach S, Noreng MF, Tjellden NU: Phantom limb pain in amputees during the first 12 months following limb amputation, after preoperative lumbar epidural blockade. Pain 33:297-301, 1988 24. Jacobson L, Chabal C, Brody MC: Relief of persistent postamputation stump and phantom limb pain with intrathecal fentanyl. Pain 37:317-322, 1989 25. Jacobson L, Chabal C: Prolonged relief of acute postamputation phantom limb pain with intrathecal fentanyl and epidural morphine. Anesthesiology 71: 984-985, 1989 26. Jacobson L, Chabal C, Brody MC, et al: A comparison of the effects of intrathecal fentanyl and lidocaine on established postamputation stump pain. Pain 40: 137-141, 1990 27. Marsland A, Weeks J, Atkinson R, et al: Phantom limb pain: a case for B-blockers? Pain 12:295-297, 1982 28. Patterson JF: Carbamazepine in the treatment of phantom limb pain. South Med J 81:1100-1102,1988 29. Logan T: Persistent phantom limb pain: dramatic response to chlorpromazine. South Med J 76:1585, 1983 30. Urban BJ, France FD, Maltbie AA, et al: Long-term use of narcotic/antidepressant medication in the management of phantom limb pain. Pain 24:191-196, 1986 31. Freed S: Acupuncture as therapy of traumatic affective disorders and of phantom limb pain syndrome. Acupuncture and Electra-Therapeutics Res Int J 14: 121-129, 1989 32. Finsen V, Persen L, LovLien M, et al: Transcutaneous electrical nerve stimulation after major amputation. J Bone Joint Surg (Br) 79:109-112, 1988 33. Weinstein S: Neuropsychological studies of the phantom. In Benton AL (ed), Contributors to Clinical Neuropsychology. Chicago, Aldine, 1969 34. Sherman RA, Gall N, Gormly J: Treatment of phantom limb pain with muscular relaxation training to disrupt the pain-anxiety-tension cycle. Pain 6:47-55, 1979 35. Iacono RI’, Linford J, Sandyk R: Pain management after lower extremity amputation. Neurosurgery 20:496-500, 1987 36. Saris SC, Iacono RF’, Nashold BS: Successful treatment of phantom pain with dorsal root entry zone lesion coagulation. Appld Neurophysiol51:188-197, 1988 37. Mundinger F, Neumuller H: Programmed transcutaneous (TNS) and central (DBS) stimulation for control of phantom limb pain and causalgia: a new method for treatment. In Siegfried J, Zimmerman M (eds), Phantom and Stump Pain. New York, Springer, 1981, pp 164-178
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38. Krainick JU, Thoden U: Spinal cord stimulation in postamputation pain. In Siegfried J, Zimmerman M (eds), Phantom and Stump Pain. New York, Springer, 1981, pp 163-166 39. Ward NG, Bloom VL, Dworkin S, et al: Psychobiological markers in coexisting pain and depression: toward a unified theory. J Clin Psychiatry 43:32-41, 1982 40. Siever LJ, Davis KL: Overview: toward a dysregulation hypothesis of depression. Am J Psychiatry 142: 1017-1031, 1985
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41. Dufton BD: Depression and the mediation of chronic pain. J Clin Psychiatry 51:248-250, 1990 42. Feinmann C: Pain relief by antidepressants: possible modes of action. Pain 28:1-8, 1985 43. Blegan A, Samuel D: Interaction of tricyclic antidepressant with opiate receptors. Biochem Pharmacol 29:460-462, 1980 44. Roman0 JM, Turner JA: Chronic pain and depression: does the evidence support a relationship? Psychol Bull 9718-34, 1985
Pathophysiology and Management of Phantom Limb Pain David D. Harwood, M.D., Sai Hanumanthu, Alan Stoudemire, M.D.
Abstract: Phantom pain phenomenon is a poorly understood but relatively common sequela of limb amputation that may result in significant psychological and physical morbidity. ln this review, proposed pathoneurophysiological mechanisms for the development of phantom pain are reviewed as well as psychological mechanisms that may be involved. The authors recommend an integated approach to management of chronic phantom pain that takes into consideration the multiple factors that may contribute to its etiology.
Introduction Phantom limb pain is a frequent sequela of amputation [l-4]. Estimates on the number of surgical and traumatic amputations of both major (limbs) and minor (digits) extremities from 1981 to 1987 show approximately 230,000 surgical amputations per year and an average prevalence of injuries resulting in amputation of 6.0/1000 persons per year, or a total of 1.3 million traumatic amputations per year [l]. Recent amputee surveys estimate that From the Department of Psychiatry, Air University (AU) Regional Hospital, Maxwell Air Force Base, Montgomery, Alabama (DDM, SH); and the Medical-Psychiatry Unit, Emory University Hospital and Emory University School of Medicine, Atlanta, Georgia (AS). Address reprint requests to: Alan Stoudemire, M.D., Emory Clinic-5th Floor, Psychiatry, 1365 Clifton Road, N.E., Atlanta GA 30322. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of Defense or the US Government. Generd Hospital Psychiatry 14, 107-118, 1992 0 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
B.A., and
60%-80% of all limb amputees experience phantom pain [l-3]. In a 1984 survey [5] of chronic phantom and stump pain among American veterans, it was found that the majority (35%) of amputees who reported phantom limb pain indicated that they were hindered by pain for 2-5 days per month. Twenty-seven percent mentioned a period of greater than 20 pain days per month [1,2]. Although phantom pain phenomena have attracted the interest of scientific investigators from many disciplines, there has been a striking lack of systematic studies of this subject [1,2]. The purportedly “indelicate” nature of the subject matter may have led Dr. S. Weir Mitchell in 1866 to report his observations of phantom limb pain anonymously, in a lay periodical [6]. The current literature on phantom limb phenomena is sparse and contradictory, reflecting only partial understanding of underlying mechanisms. Most clinical reports are based mostly on short-term studies with small groups [1,2]. It is important to note that the term “phantom pain” subsumes several distinct pain sensations. Mechanisms thought to influence one type of phantom pain may or may not be involved in a different type of sensation. Insufficient attention to subtyping the painful sensations in the medical literature has contributed to the unsatisfactory nature of attempts to explain the entire phenomenon of phantom pain. In order to clarify discussion of phantom pain
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symptoms, Ribbers et al. [2]. have suggested the following definitions: Phantom: The continuous awareness of a (or part of a) nonexisting or deafferented body part with specific form, weight, or range of motion. Phantom Sensation: Each nonpainful sensation of the phantom. Phantom Pain: Each painful sensation felt in the stump (e.g., pain due to neuromata, exostoses, postoiera&e pain, and pain caused by abnorma1 sensitivity termed allodynia [2]. This article will review the current literature describing the psychological and physiological factors thought to be relevant in phantom pain, as well as discuss treatment strategies that have been recommended for its management.
Literature Review First reported by Ambrose Pare in 1551 [2], descriptions of phantom pain have been largely consistent among most amputees. Typical painful feelings include 1) shooting/shocking, 2) cramping, 3) stabbing, 4) burning, and 5) squeezing [l]. A central feature is a “tingling feeling and a definite shape that resembles the somatosensory experience of the real limb before amputation” [4]. There is also growing evidence of phantom phenomena in amputated parts other than limbs. Kroner, et al., described a 25.8% incidence of “phantom breast syndrome” among 120 women following mastectomy [7]. Reported by 70% of amputees in the first few weeks after amputation, phantom limb pain persists in approximately 50% even 7 years after amputation [4]. Several theories have been proposed to account for this phenomenon. It has been suggested that preoperative limb pain plays a role in phantom pain immediately after amputation, but probably not in late persistent phantom pain. In a prospective study of 58 patients undergoing limb amputation, it was found that during the first six months after limb loss phantom pain was significantly more frequent in patients with long-lasting preamputation limb pain and in patients with pain in the limb immediately prior to amputation than in patients without preoperative pain. Phantom pain and preamputation pain were similar in both localization and character in 36% of patients immediately after amputation but in only 10% of patients at six months’ followup [8]. 108
Kroner et al. found similar results in a prospective study of 120 women undergoing mastectomy. The authors, based on their findings, postulated that “constant painful sensory input prior to amputation established a long-lasting sensory engram in the brain’ [7].
Neurophysiological Mechanisms Based on earlier work with Loeser on paraplegics, Melzack [4] proposed a neurophysiological theory involving the concept of a neuromatrix, defined as “a network of neurons that extends throughout widespread areas of the brain, composing the anatomical substrate of the physical self.” Melzack suggested that the neuromatrix, which subserves body sensation, has a “genetically determined substrate that is modified by sensory experience.” According to this explanation, “loss of modulating input from limb or body causes the neuromatrix to produce an abnormal signature pattern created by the patterns that flow through the neuromatrix.” The result of the insult on the signature pattern is that it “subserves the physiological qualities of heat or burning-the most common qualities of phantom limb pain.” This neuromatrix is thought to be genetically determined, as even children born without limbs have occasional phantom phenomena . The neuromatrix is not structurally confined to the “somatosensory cortex,” as excision of this brain structure does not prevent the eventual reappearance of phantom sensations, including pain. Melzack [4,9] suggested that the neuromatrix comprises a complex interplay of neural systems, or “substrate of the physical self,” including thalamocortical, limbic, and occipital components. The concept as presented is elegant in that emphasis is shared between peripheral and central mechanisms. Melzack cautions against attributing exclusive explanatory value of peripheral neurovascular mechanisms in pain perception; that is, despite the vaguely defined nature of neuromatrix, sensory ingrams, morphogenetic fields, and so forth, it is certain that the brain and its subsystems are critical in centrally modulating input. As Figure 1 indicates, a host of other theoretical mechanisms have been offered to explain the development of phantom phenomena. It is useful to sort them by their purported anatomical foci relating to 1) the periphery, 2) the spinal cord, 3) the autonomic nervous system, and 4) changes up to
Phantom
MECHANISMS THEORETICALLY INVOLVED IN PHANTOM LIMB PAIN
5,6
-1,2,3,4 Figure 1. Proposed sites for the neuropathophysiology of phantom limb syndrome. Key: 1) Neuroma information; 2) Vascular changes; 3) Pressure receptor changes; 4) Local chemical changes; 5) Degenerative changes at spinal and supra spinal levels; 6) Microvascular changes in spinal cord blood supply; 7) The “Neuromatrix”
the level of the spinal cord (central
PI.
mechanisms)
Advocating the predominant role of a peripheral mechanism in the etiology of phantom limb pain, Jensen et al. [lo] and Ribbers et al. [2] reported that manipulation of the stump influences phantom pain. Wall [ll] and Ribbers et al. [2], in earlier experimentation in animals immediately postamputation, revealed multiple nerves sprouting at the stump end, resulting in abnormal and erratic local It was proposed that newly depolarizations. formed nerve bulbs in recovering tissue are more sensitive to the locally elevated levels of tissuerelated growth and pain-modulating factors leaking into the immediate environment due to the damaged blood-nerve barrier [2,11]. This presumed that an increase in the sprouting of small cutaneous nerves in the skin flaps might be a causal
Pain Pathophysiology
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factor in the short-term postoperative development of burning or cramping pain (probably from chaotic large-muscle activity by aberrant local nerve input) 12,111. Skepticism exists, however, on how much importance should be attributed to peripheral mechanisms. An alternative explanation to the findings of Jensen et al. [S] is in terms of “altered afferent input into a central system” [2]. Further, phantom sensation in cases of spinal anesthesia (where there is no nerve damage or regenerative sprouting) demonstrates that peripheral mechanisms may not necessarily play a major causal role in this type of phantom pain development [2]. Evidence from the model of local anesthesia (which can result in phantom sensations other than pain) provides indirect support for the role of spinal cord mechanisms in the pathogenesis of phantom pain [2,11]. Ribbers et al. [2] offer the example of an apparently swollen cheek after dental anesthesia. Because anesthesia makes depolarization impossible, and the time of phantom onset is not sufficient for any known chemical substance to traverse the area of the block to the spinal cord, the pain was believed to be the result of disinhibition of active spinal cord neurons. Distinct changes at the level of the spinal cord after section of a peripheral nerve have been reported by Wall as “immediate” and u11 and characterized “chronic” changes. Immediate changes involve an increased excitation of partly afferent cells due to disinhibition and the regeneration of receptive fields in cells. The chronic pattern involves changes in metabolism, along with chemical and morphological changes in the afferent terminals of the spinal cord. After 10 days, changes in cellular peptide concentration within the dorsal horn imply that “the effect of the peripheral nerve lesion has spread beyond the damaged cells into the spinal cord mechanism itself” [2,11]. An alternative pathway thought to influence phantom pain involves autonomic nervous system fibers, which are primarily linked to blood vessels (including small capillaries and larger arteries) that completely bypass the spinal cord. As proposed by Lawrence [12], these fibers would transport pain impulses directly to higher structures of the central nervous system [2]. Evidence cited to support this theory is based on the observation that relief of pain (thought to be secondary to long-term changes in blood flow) accompanies perivascular sympathectomy. Modulation of the perivascular fibers, then, should also influence phantom pain if such 109
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a connection does indeed exist. In paraplegics, for example, the stimulation of the perisosteum of the vertebrae, an area richly innervated by sympathetic fibers and linked above and below the level of transection by blood vessels “eliminated phantom pain for varying periods of time” [2,12]. It is unlikely, however, that disinhibited autonomic neurons are the primary cause of phantom pain. As has been observed, “If phantom pain could be explained in terms of disinhibited spinal cord neurons, it should be possible to provoke it by local anesthesia. Such a phenomenon has not yet been described” [2]. In other words, phantom sensations do not necessarily lead to the development of phantom pain. A “central” explanation is proposed by Katz and Melzack [13] who report that referred sensations (paresthesias, pain, temperature changes, pressure, or constriction) were experienced in a sample of 98 chronic pain patients during electrical stimulation applied at the outer ears, face, and torso. This theory proposes that somatosensory input from the area of electrical stimulation targets excitatory neuron pools in the central nervous system, resulting in “multiple sensations that are perceived to originate in the periphery.” “Deafferentation due to disease, injury, or lesions of the central nervous system lead to a hypersensitivity and an increased likelihood of referred pain of long duration” [ 131. Further evidence of a central mechanism arises from observations of transneural changes up to the level of the thalamic nuclei following deafferentation, and the observation that the nature of chronic pain is similar to thalamic pain syndrome and anesthesia dolorosa [ 14,151. The specific neurophysiological systems involved in referred pain phenomena require substantial elucidation at the basic science level, but the models presented above are clearly the most persuasive examples available for a tentative understanding of the various phantom pains.
for different people, depending on such factors as the sex, age, and occupation of the individual. For example, amputation may have greater significance for the elderly because “it seems to symbolize the encroachment of death.” As Caplan and Hackett [16] observed, “the fact that a part of {him} has died and been destroyed makes all too vivid the stark realization that the rest of the body is equally vulnerable and disposable.” The loss may thus be overtly manifest as fear over the apparent imminence of death, imparting sadness in the life, job, family, and social interactions of the individual. Parkes [2,17,18]. viewed the grief associated with the loss of limb as part of the mourning syndrome: “Just as the widow finds it hard to believe that her husband is dead and often has a strong sense of his presence, so the amputee has difficulty in accepting the loss of his limb and he continues to feel that it is present.” Mitcherlich [19] considered the phantoms to be “the result of a conflict between the archaic present desire for regeneration and the definite acceptance of the loss of the amputated limb” [16]. Frazier and Kolb [20] proposed three psychological factors thought to be most important in the etiology of phantom pain: “unresolved fantasies about the amputated limb, previous association with an amputee, which was frequently morbid, and overemphasis on bodily parts.” There have been no correlations in the literature between “heavily emphasized body parts” and the frequency of phantom pain. Other authors believed that people with “rigid’ and “compulsive selfreliance” profiles on psychological testing seem to have more persistent pain [20]. In an analysis of the literature on psychological factors influencing phantom limb pain, Sherman [21] concluded that chronic phantom limb pain is “magnified” by stress, anxiety, and depression, but there is no evidence to suggest an increased incidence of anxiety or depressive-spectrum disorders in amputees with phantom pain.
Psychological Aspects
Reported Treatments of Phantom Limb Pain
In addition to neurophysiological explanations of phantom pain, the psychological aspects of limb loss have been explored from many perspectives. The psychodynamics of limb loss seem most useful clinically as a means of understanding the patient’s total experience, and notably less helpful when
Sherman [21] identified 43 individual treatments purporting to successfully treat phantom limb pain. The following discussion highlights several treatment strategies (Table 1). It should be noted, however, that most of these reports, several of which will be outlined below, consist of small numbers of patients in open treatment trials without placebo controls.
they imply causality in specific physiological sensations. The loss of a limb has different meanings
110
Excellent anesthetic with no trace of PLP until the block began to wear off. Pain was more severe and in a different site than the usual phantom. “Heel pain” ceased within 5 minutes of completion of the infusion. Only two fleeting episodes occurred over the next 12 hours. They were left untreated and mild nausea was reported. TENS is initially effective for phantom pain. No difference between placebo and actual treatment groups after 1 year. No differences in pain until after 4 months following treatment when phantom pain prevalence was significantly lower with active TENS treatment. No complications related to the technique were observed.
Case report, n = 1. Epidural anesthesia for C-section. Total dose of 26 ml of 0.5% bupivacaine given in increments over a 1 hour period. Case study, n = 1. 100 IU salmon calcitonin was given intravenously over 5 minutes.
Placebo controlled, n = 51. Long-term follow-up of TENS. Unblinded. Fifty-one patients were randomized: SHAM TENS and chlorpromazine. SHAM TENS (control). Low frequency TENS-active (more rapid stump healing).
Controlled pilot study, II = 11. Retrospective control goup. Continuous regional analgesia by nerve sheath block for lower limb amputation. Continuous infusion of 0.25% bupivacaine at 10 ml/hour for 72 hours. Demanded 1.4 mg of morphine compared to 18.4 mg for the control.
Carrie et al
Fiddler et al
Finsen et al
Fisher et al
Author At 1 year, three of controls had phantom pain, none of the blockaded patients did.
(PLP).
Controlled randomized trial, n = 25. Performed lumbar epidural blockades before amputations on 11 of 25 elderly patients. Unblinded.
limb pain
Bach et al
for uhantom Outcome
treatments MethodlTechniaue
Table 1. Selected
Follow-up of the group for up to 12 months showed total absence of pain despite the presence of preoperative limb pain.
Clinical experience suggests TENS is still a good way to disrupt a chronic pain pattern.
Follow-up over several months showed a return to baseline PL status. Calcitonin may act via serotonergic mechanisms to increase the activity of descending pain suppressing systems and thereby inhibit transmission of PLP.
Epidural anesthesia did not produce phantom pain during its period of action as reported under spinal anethesia.
Reducing preoperative pain thought to result in the difference.
Comment
Intravenous subanesthetic dose of thiopental should be tried immediately when I’LP occurs during spinal anesthesia.
Nine patients responded immediately and noted a clear analgesic effect.
Pain was completely short term.
Thirty years of persistent phantom pain abated completely. Side effect; patient had diminished ability to calculate. Successful short-term with propranolol.
Controlled study, n = 10. Immediate response of phantom limb pain to calcitonin after a single injection. Patients with persistent or acute PLP. Case study, n = 3. Intravenous subanesthetic doses of thiopental in several patients with previous lower limb amputations. Case study, n = 1. Persistent PLP. Dramatic response to chlorpromazine in 56-year-old female. Case study, n = 3. Treatment for burning phantom pain; Bblockers.
Kessel and Worz
Koyama et al
Logan, T.
Marsland
et al
et al
Jacobson
treatment
abolished
Fast reaction, within 5-30 minutes. Optimal dosage is yet to be determined. Lasted from 2 hours to 3 months. Side effects.
Fentanyl always abolished pain. Median analgesia duration for 8 hours. Lidocaine relieved discomfort but did not abolish the pain.
Case study, n = 8. Comparison of 25 pg lumbar intrathecal fentanyl and 70 pg lidocaine 2 weeks apart.
et al
Jacobson
Supports the claim of a vascularrelated mechanism for burning phantom pain.
Authors conclude the case points to a central mechanism of pain.
Primary importance is given to a central mechanism involving the spinal cord in the modulation of established stump pain in the eight subjects.
Neuraxial. Intrathecal and epidural fentanyl produced its good effects by segmental spinal action. Spinal modulation was important to postamputation pain.
Temporarily abolished the pain, normalized sensations. Produced euphoria without supraspinal efects.
Case study, n =2. Intrathecal fentanyl 25 pg to postamp PLP and stump pain patients, respectively. Intrathecal fentanyl at various doses on one patient.
Comment
Outcome
Author
Method/Technique
Table 1 (continued)
5
W
Urban, B. J. et al Consecutive case, 12 = 5. Uncontrolled. Used methadone and doxepin in variable doses (methadone 1520 mg daily; doxepin 25-150 mg daily).
Case study, n = 16. Biofeedback.
et al
Sherman
Case study, n = 1. Carbamazepine in the treatment of PLP.
Case study, II = 22. All underwent Dorsal Root Entry Zone (DREZ). Six months to 4 years followup.
J. F.
Saris et al
Patterson,
Greater than 50% improvement in pain control in all five patients at 22 months.
Biofeedback training designed to reduce muscle tension led to long-term reduction or disappearance of phantom pain.
Eight of 22 had pain relief, 6 of 9 PLP patients had relief, and 5 of 6 with traumatic amputations associated with root avulsion had relief. Poor results for patients with both stump and PLP or stump alone.
As the carbamazepine level approached therapeutic levels, the patient became less concerned with his pain, though it was still present. When treatment stopped, pain returned.
No problems with abuse/ tolerance of narcotics. All patients had failed previous treatment regimens.
General correlation between intensity of cramping phantom pain and intensity of muscle tension. Conclude that chronic phantom pain is affected by stress, anxiety, and depression.
DREZ procedure has a welldefined but limited role in postamputation treatment.
Experience to date indicates the need for controlled doubleblind crossover studies to test therapeutic validity.
D. D. Harwood et al.
Parenteral and spinal injection strategies. Calcitonin represents a novel approach for phantom limb treatment. Following a single intravenous injection of 100 IU of calcitonin to 10 patients with persistent or acute phantom limb pain, nine patients responded immediately with diminished pain. A control group of nonphantom pain patients did not respond at all, except for one patient with chronic stump pain. Within 5-30 minutes, relief of pain was noticed; the therapeutic effect was attributed to activation of a central inhibitory system. The optimal dose of calcitonin is still open, given significant side effects of dysesthesia, nausea, and vomiting [ZZ] . In a randomized, prospective trial in which lumbar epidural blockades were performed prior to amputations on 11 of 25 patients, at 1 year, none of the 11 blockade patients and 3 of the 14 controls had phantom pain. In this study, 11 patients were given active epidural blockades and 14 were given sham treatment. The difference was attributed to reduced preoperative pain in the active group [23]. In an uncontrolled series of two patients with postamputation stump and phantom limb pain, Jacobson et al. [24] reported that intrathecal fentanyl was able to transiently abolish the painful sensations without producing supraspinal effects. The authors also found that intravenous fentanyl and intravenous lidocaine were unable to reproduce the anesthetic effects derived from intrathecal administration. They suggest that segmental spinal action with spinal modulation of postamputation pain was responsible for the differential response, and that this demonstrates the predominant role of spinal vs peripheral mechanisms in the etiology of phantom limb pain. In another case report involving an amputee with “severe and intractable acute postamputation phantom foot pain,” Jacobson and Chabal [25] were able to “extinguish established phantom limb pain and restore normal sensations for about 8 hours.” Prior to an intrathecal injection of fentanyl, a number of pain treatments (morphine, meperidine with hydroxyzine, patient-controlled intravenous analgesia with morphine, and oxycodone with acetaminophen) proved ineffective. Following the single dosage of intrathecal fentanyl 25 mg, epidural morphine (5 mg) therapy was injected every 12 hours via the epidural catheter for 11 days, during which time there was no recurrence of phantom pain. Given the fact that significant changes take place in spinal cord areas dense with opiate receptors following peripheral nerve tran114
section, opioids may “offer the potential for effective treatment and prophylaxis of postamputation pain” [25]. In a comparative, single-blinded, controlled study reporting the effectiveness of intrathecal lidocaine and fentanyl on established postamputation stump pain, Jacobson et al. [26] administered lumbar intrathecal fentany125 mg and lidocaine 70 mg 2 weeks apart to eight patients with established lower limb postamputation stump pain. In contrast to intrathecal lidocaine which served only to relieve the discomfort, intrathecal fentanyl was able to “abolish” the pain such that analgesia was complete by 5-10 minutes following administration and lasted a median of 8 hours. With lidocaine, the median duration of analgesia was 2 hours, and pain was not abolished in three of eight patients. In accordance with earlier studies, the authors suggested that intrathecal fentanyl provided analgesia via a segmental spinal action, and that “through its action on spinal opioid receptors, subarachnoid fentanyl altered the impulse pattern signaling pain in a way that was perceived as pleasant.” This study once again redirects attention from peripheral mechanisms to central mechanisms involving the spinal cord and to the potential importance of spinal opioids in further elucidation and therapy of postamputation stump pain [26].
Oral pharmacological strategies. Short-term success for burning phantom pain has been achieved with beta-adrenergic blocking agents, particularly strongly lipophilic agents like propran0101.The improvement reported with beta-blockers implies support for the claim of a vascular-related mechanism for burning phantom pain, with implications for use of sympathetic blocks and sympathectomy to increase blood flow to the limbs [27]. Carbamazepine and chlorpromazine have had good therapeutic results. In a case reported by Patterson [28], as carbamazepine levels approached therapeutic levels, the patient became less concerned with his pain, although it was still present. At blood levels of 4 ng/ml, pain was present but not readily noticed. At 10 ng/ml, pain was totally ablated. When treatment was stopped, pain returned. In a single-case report, a 56-year-old female who was suffering from 30 years of persistent, severe phantom pain became free of pain after treatment with chlorpromazine [29]. The use of anticonvulsants and neuroleptics in phantom limb pain is unsubstantiated by formal studies but sug-
Phantom Pain Pathophysiology and Management
gested by inference from the literature on neuropathic and other chronic pain states. When Urban et al. [30] treated five consecutive patients with “intractable” phantom limb pain with methadone 15-20 mgld and doxepin 25-100 mgld, a greater than 50% reduction in pain was demonstrated, which was maintained over the course of 2 years. No associated problems (tolerance, abuse) were noted from the narcotic use [30]. Other treatments. Freed [31] recently presented a review of acupuncture treatment for phantom pain, relating the purported effectiveness to a bodachieved with acupuncture. This ily “stillness” stillness was thought to be related to 1) alpha rhythm prominence on electroencephalogram, 2) deep general relaxation, 3) an increased pain threshold, and 4) total body involvement. This idea requires empirical testing before it can be critically addressed. Transcutaneous electrical nerve stimulation (TENS) has been reported to be initially effective for phantom pain. In a study involving 51 patients who had undergone major amputation of the lower limb, Finsen et al. [32]. reported that “the prevalence of phantom pain after active TENS was significantly lower after 4 months but not after more than 1 year” [33]. In an uncontrolled study designed to reduce muscle tension in 16 phantom limb patients, biofeedback training led to long-term reduction or disappearance of phantom pain in 14 of the 16 patients. A general correlation was observed between the intensity of cramping phantom pain and the intensity of muscle tension [34]. Neurosurgery. Iacono et al. [35] recently reviewed surgical treatments available for phantom limb pain. A broad range of treatments have been employed including stump revision, neuroma resection, cordotomy, mesencephalotomy, and dorsal rhizotomy, none of which were recommended. Surgical options possibly effective after exhausting all available nonsurgical modalities include 1) direct peripheral nerve stimulation, 2) spinal cord stimulation, 3) deep brain stimulation, and 4) spinal dorsal root entry zone lesion (DREZ). Surgical procedures such as thalamic surgery, cordotomy, sympathectomy, nerve strangulation above the stump end, and surgery at the stump have received mostly negative reviews. There are few details on procedures to alter physically interpretive centers of the brain. The few successes
that are reported are confined to case studies with minimal follow-up [21]. Savis et al. [36], in an uncontrolled series of 22 patients with postamputation stump pain and phantom limb pain treated with DREZ, found 36% (8/22) had significant pain relief at follow-up from 6 months to 4 years. It was noted that 67% (6/9) of patients with phantom pain alone experienced significant improvement, whereas none of the six patients with stump pain alone experienced improvement. This implies central and peripheral origins for phantom and stump pain, respectively, and suggests that peripheral nerve stimulation may be useful for stump pain management. Deep brain stimulation, chiefly of the thalamus, periventricular gray, and internal capsule produced significant improvement in 86% of a population of 30 patients with intractable phantom pain ]371. Invasive spinal cord stimulation was studied in an uncontrolled fashion with 64 patients, 52% of whom reported good results at 2-year follow-up, with much less improvement noted for stump pain J381. As this catalog of treatments suggests, successful rehabilitation is dependent upon medical, social, psychological, and vocational factors, and no single factor judged independently guarantees a meaningful rehabilitation.
Discussion To illustrate a practical approach to the management of phantom limb pain, a typical case from our practice illustrates the management of phantom pain that did not require invasive anesthetic techniques.
Case Hishy Ms. J, a healthy 27-year-old, received multiple injuries in a motor vehicle accident, including a traumatic below-the-knee (BRA) amputation of her right leg. One month postinjury we were consulted to assist in pain management. The patient was experiencing persistent frequent “electricity-like” pain in her right stump, “lower leg,” and “foot,” as well as episodic “crushing” pain in the stump and calf area. She was also found to have developed a concomitant depressive disorder. When her pains had been unimproved by trials of several nonsteroidal agents, low-dose narcotics, and TENS, as well as homeopathic doses of amitrip115
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tyline, Ms. J was begun on doxepin, which was titrated over several days to 150 mg/day. Regular schedules of a potent oral narcotic, hydromorphone 2-4 mg every 4 hours, and ibuprofen 800 mg every 8 hours, replaced the oxycodone/acetaminophen she had been receiving p.r.n. The patient, family, and staff were educated about phantom pain and physical therapy (including massage, graded exercise, and hydrotherapy) before it was initiated. The pain relief was rapid, particularly the crushing pain. The depressive symptoms resolved over several weeks, and 6 months postoperatively she was tapered off the narcotic without recurrence of pain. She was seen weekly throughout this time frame in supportive psychotherapy where education, family involvement, and exploration of the meaning(s) of her loss of body integrity/function were prominent features. As illustrated in the above case, our approach to the treatment of phantom pain employs multiple interventions from several disciplines. As our patient felt “suspect” in her complaints and the ward staff was becoming impatient with her progress, education assumed a primary role in reducing the tension. Through discussion of the complex nature of phantom pain, the patient experienced a dramatic reduction in the “vague notion” that she was psychologically unstable. A strictly “medical” (e.g., neurophysiological) model of phantom pain was presented, and the initial recommendation was vigorous, scheduled treatment with a potent narcotic known to the staff as a medication for “serious” pain. Medication p.r.n. was discontinued because it seemed to result in undermedication and increased frustration for both the patient and the staff. The patient’s positive symptom relief reinforced this approach. Full psychiatric evaluation revealed a concomitant mood disorder which was treated in an aggressive standard manner. The course of treatment showed that reducing the symptoms of the mood disorder correlated in time with decreased pain (vs lowered sensitivity). Physical therapy was immediately involved for the future-oriented tasks of vigorous rehabilitation and eventual prosthetic use. Finally, joint sessions with the patient and her husband were utilized to support their adaptation and anticipate potential problem areas. One possible explanation for the successful outcome in our example case was doxepin’s presumed ability to “reregulate” a dysregulated amine-
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mediated system (the paleospinothalamic tract, PSTT) that produced both pain and disordered mood [39-411. In addition, tricyclic antidepressants, including doxepin, may directly relieve pain by altering brain levels of biogenic amines, specifically serotonin and norepinephrine, which are thought to modulate pain perception and sensitivity [42]. Doxepin may also enhance the bioavailability of both naturally occurring endorphins and enkephalins and opiate analgesics by direct binding to opiate receptors in the brain [42,43]. This may explain the maintenance of pain relief when the hydromorphone was discontinued. The patient herself assumed a more psychological explanation: she felt that as her depression resolved she was more able to tolerate the residual phantom pain, had more capacity to distract herself, and became less inclined to be preoccupied with pain. The nature of the association, if any, between chronic pain and depression is unclear and controversial [44]. Ward, et al. [393 have suggested that certain types of pain (chiefly tonic, dull, burning and poorly localized sensations) are mediated by the PSTT which may be affected by the same imbalance of biogenic amines thought to be involved in the onset of depression [39]. This is the type of pain typically associated with phantom phenomena.
Summary The difficulties in formulating a comprehensive explanation for phantom pain with subsequent generation of testable hypotheses regarding treatment may be one of definition. As alluded to earlier, our suspicion is that there are several types of phantom pain, mediated differently with different causal contributions and different responses to treatment. It is clear that phantom pain is a clinical event wellsuited to the “biopsychosocial” model, with fundamental neurophysiological events manifesting themselves in multiple areas of the patient’s life. Further, individual treatment modalities of all types, from psychoanalysis to aggressive neurosurgical procedures, have had predictably unsuccessful outcomes. The literature, as reviewed here, reveals a paucity of both basic research and clear clinical guidelines for the treatment of patients with phantom pain. Given the significant incidence of this problem and the uniformly poor interventions to date (beyond the isolated case report), further research into the specific brain events mediating
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carefully delineated types of painful sensations is needed.
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