Chronic postamputation pain

Treatment of chronic postamputation pain represents a major challenge to the clinician and in particular the treatment of phantom pain. There is only little evidence from randomized trials to guide clinicians with treatment, and most studies dealing with phantom pain suffer from major methodological errors: samples are small, randomization and blinding are either absent or inappropriate, controls are often lacking, and follow-up periods are short. Halbert et al.83 performed a systematic literature search to determine the optimal management of phantom pain. The authors identified 186 articles, but after exclusion of letters, reviews, descriptive trials without intervention, case reports, and trials with major methodological errors, only 12 articles were left for review. Since then, some well-designed studies have been published.78,

, , , , , , , , Until more clinical data become available, guidelines in analogy with treatment regimens used for other neuropathic pain conditions are probably the best approximation, especially for the treatment of residual limb pain. A combination of medical and nonmedical treatment may be advantageous. In general, treatment should be noninvasive. Surgery on the peripheral or central nervous system always implicates further deafferentation and thereby an increased risk of persistent pain. Suggestions for treatment of postamputation pain are presented in Table 31.3.

MEDICAL TREATMENT

A large number of randomized controlled trials have shown a beneficial effect of tricyclic antidepressants and sodium channel blockers in different neuropathic pain conditions.5[I] Only few controlled data are available for phantom pain, but the drugs are generally believed to be effective, at least in some patients.

A recent study examined the effect of tricyclic anti-depressants on phantom pain.88[II] Thirty-nine patients were randomized to receive either amitriptyline or active placebo during a six-week trial period. The dosage of amitriptyline was increased until the patient reached the maximum tolerated dose or 125mg/day. Unfortunately, this study showed no effect of amitriptyline on pain intensity or secondary outcome measures, such as satisfaction with life. In contrast, Wilder-Smith et al.89 found excellent pain relief of amitriptyline (mean dose, 55 mg) on both residual limb and phantom pain. Ninety-four posttraumatic amputees were randomized to receive

Table 31.3 Suggestions for treatment of postamputation pain (not evidence-based). Postamputation pain

Early postoperative pain

Residual limb pain: Conventional analgesics (paracetamol, NSAIDs, opioids), perhaps combined with regional blocks Residual limb and phantom pain: In case of clear neuropathic pain signs - paroxyms or abnormal residual limb sensitivity - tricyclic antidepressants or anticonvulsants can be tried

Chronic pain

Local residual limb surgery: If obvious stump pathology is present, residual limb revision should be considered. Surgery should be avoided in chronic regional pain syndrome Local medical treatment: Topical lidocaine/capsaicin can be tried in cases with residual limb pain without clear stump pathology

Residual limb and phantom pain (medical treatment, listed in order of preference)

1. Tricyclic antidepressants (imipramine, amitriptyline, nortriptyline) 10-100 mg/day, start dose 10-25 mg/day, weekly increments of 25 mg.

Check ECG before start. Monitor plasma levels with dose >100 mg/day. Amitriptyline should be preferred if sedation is wanted

2. Gabapentin 1200-2400 mg/day, start dose 300 mg, increments of 300 mg every 3rd day, maximum dose 3600 mg/day Pregabalin 75-600 mg/day, start dose 25-75 mg, increments of 75 mg/day every 3rd day, maximum dose 600 mg/day

3. Serotonin noradrenaline reuptake inhibitors Venlafaxine 175-225 mg/day, start dose 75 mg Duloxetine 30-60 mg/day, start dose 30 mg

4. In cases of mainly radiating, lancinating or paroxysmal pain:

(a) Oxcarbazepine 600-900 mg/day, start dose 300 mg, weekly increments of 300 mg

(b) Carbamazepine 200-400 mg/day, start dose 100 mg, weekly increments of 100 mg. Monitor plasma levels after 10 days on maximum dose

(c) Lamotrigine 100-200 mg/day, start dose 25 mg/day, slow titration with increments of 25mg/14days (to avoid rash)

5. Opioids (long-acting or sustained-release preparations) or tramadol

6. No effect of the above: Consider referral to pain clinic

ECG, electrocardiogram; NSAID, nonsteroidal anti-inflammatory drugs.

amitriptyline, tramadol, or placebo for one month. The administration of tramadol and placebo was blinded, amitriptyline was given nonblinded as open comparison. Nonresponders (less than 10 mm pain relief on a VAS from baseline on day three) were switched to the alternative active treatment, e.g. tramadol to amitriptyline treatment and vice versa. Placebo nonresponders were switched to tramadol or amitriptyline. Both tramadol and amitriptyline almost abolished residual limb and phantom pain at the end of the treatment period.89[II]

Bone et al.84[II] examined the effect of gabapentin in a well-designed crossover study including 19 patients with phantom pain. The dose of gabapentin was titrated in increments of 300 mg to a maximum dosage of 2400 mg per day. After six weeks of treatment, gabapentin was better than placebo in reducing phantom pain. A similar effect of gabapentin was described in an open study by Rusy et al.93 [V] Two other studies have recently examined the effect of gabapentin on postamputation residual limb and phantom pain. Smith et al.90 [II] administered gabapentin or placebo for six weeks to 24 amputees in a double-blind crossover fashion. The maximum dose given was 3600 mg. Gabapentin did not decrease intensity of pain significantly, but the participants rated the decrease of pain as more meaningful during the treatment period with gabapentin. All the above-mentioned studies examined the effect of gabapentin on established phantom pain. Nikolajsen et al.91 [II] randomized 46 lower-limb amputees to receive either gabapentin or placebo for the first 30 days after amputation. The first dose of 300 mg gabapentin/placebo was given on the first postoperative day, and the dosage was gradually increased until a maximum of 2400 mg was reached. Intensity, frequency, and duration of phantom pain attacks were recorded daily in the first 30 days and after three and six months. Intensity of residual limb pain was also recorded and sensory testing of the residual limb was performed. The two treatment groups were similar as regards all outcome parameters. Thus, early treatment with gabapentin started before the phantom pain becomes established does not seem to affect outcome.

Failure to provide efficient pain relief should not be accepted until opioids have been tried. Opioids can probably be used safely - with a limited risk of dependence - for several years.94[I] In a randomized, doubleblind, crossover study with active placebo, 31 amputees received a 40-minute infusion of lidocaine (lignocaine), morphine, or diphenhydramine. Compared with placebo, morphine reduced both residual limb and phantom pain, whereas lidocaine decreased only residual limb pain.87[II] In another placebo-controlled, crossover study including 12 patients, Huse et al. found a significant reduction of phantom pain during treatment with oral morphine.78[II] Case reports have suggested that methadone may reduce phantom pain.95[V]

The effect of NMDA receptor antagonists has been examined in different studies. In a double-blind, placebo-controlled study, intravenous ketamine reduced pain, hyperalgesia, and wind up-like pain in 11 amputees with residual limb and phantom pain.71[II] Two other trials have examined the effect of memantine, an NMDA receptor antagonist available for oral use. In both studies, memantine was administered in a blinded, placebo-controlled, crossover fashion to patients with established residual limb and phantom pain. Memantine at doses of 20 or 30 mg per day, respectively, failed to have any effect on spontaneous pain, allodynia, and hyperalgesia.85[II],86 [II] Schley et al.92[II] recently randomized 19 patients with traumatic amputations to receive either memantine or placebo in combination with a continuous brachial plexus blockade in the immediate postoperative phase. The dose of memantine was increased from 10 to 30 mg during the four-week treatment period. Treatment with memantine resulted in a decrease of phantom pain at four-week and six-month follow up, but not at 12-month follow up. Dextromethorphan, another NMDA receptor antagonist, was suggested to be effective in a study including ten patients with phantom pain.96[III]

Calcitonin significantly reduced phantom pain when used intravenously in the early postoperative phase.97[II] A large number of other treatments, for example p-blockers,98,99[V] the oral congener of lidocaine,100[V] topical application of capsaicin,101[V] intrathecal opioids,102[III], 103[V] various anesthetic blocks,104,105 [V] injection of botulinum toxin,106[V] and topir-amate107[V] have been claimed to be effective in phantom pain, but none of them have proved to be effective in well-controlled trials with a sufficient number of patients.

NONMEDICAL TREATMENT

A recent survey of treatments used for phantom pain revealed that after pharmacological treatments physical therapy was the treatment modality most often used.108 Physical therapy involving massage, manipulation, and passive movements may prevent trophic changes and vascular congestion in the residual limb. Other treatments, such as TENS, acupuncture,109[V] ultrasound, and hypnosis,110[V] may in some cases have a beneficial effect on residual limb and phantom pain. At least three studies have examined the effect of TENS on phantom pain, but the results are not consistent.111[II], 112[III], 113[III] One study showed an effect of a Farabloc, a metal-threaded sock to be worn over the residual limb.114 Ramachandran and Rogers-Ramachandran115[V] used visual feedback with a mirror to eliminate painful phantom limb spasms. In a larger clinical trial of 80 amputees, Brodie et al.116[II] failed to find any significant effect of mirror treatment on phantom limb pain, sensation, and movement. Flor et al. demonstrated that sensory discrimination training obtained by applying stimuli at the residual limb reduced pain in five upper limb amputees.62[III] The advantage of most of the above-mentioned methods is the absence of side effects and complications, and the fact that the treatment can be easily repeated. However, most of these studies are uncontrolled observations.

SURGICAL TREATMENT

Surgery on amputation neuromas and more extensive amputation previously played important roles in the treatment of residual limb and phantom pain. Today, residual limb revision is probably performed only in cases of obvious stump pathology, and in properly healed residual limbs there is almost never any indication for proximal extension of the amputation because of pain. The results of other invasive techniques, such as, for example, dorsal root entry zone lesions,117[V] sym-pathetectomy, and cordotomy have generally been unfavorable, and most of them have been abandoned. Surgery may produce short-term pain relief, but the pain often reappears. Spinal cord stimulation118[III] and deep brain stimulation119[V], 120[V] are methods that may be used for carefully selected patients.

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