Interventions

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Treatment of chronic postamputation pain represents a major challenge to the clinician, 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 methodologic 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. [31] performed a systematic literature search (Medline 1966-99) 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 methodologic errors, only 12 articles were left for review. Since then, some well-designed studies have been published. 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 stump 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.

Medical treatment

Tricyclic antidepressants

A large number of randomized controlled trials have shown a beneficial effect of tricyclic antidepressants in different neuropathic pain conditions. 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. Thirty-nine patients were randomized to receive either amitriptyline or active placebo during a 6-week trial period. The dosage of amitriptyline was increased until the patient reached the maximum tolerated dose or 125 mg/ day. Unfortunately, this study showed no effect of amitriptyline on pain intensity or secondary outcome measures such as satisfaction with life [32]. In contrast, Wilder-Smith et al. [33] found excellent pain relief of amitriptyline (mean dose 55 mg) on both stump and phantom pain. Ninety-four post-traumatic amputees were randomized to receive amitriptyline, tramadol or placebo for 1 month. The administration of trama-dol 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 3) 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 stump and phantom pain at the end of the treatment period.

Gabapentin

Bone et al. [34] examined the effect of gabapentin in a well-designed cross-over 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 6 weeks of treatment, gabapentin was better than placebo in reducing phantom pain. Smith et al. [35] administered gabapentin or placebo for 6 weeks to 24 amputees in a double-blind cross-over fashion. The maximum dose given was 3600 mg. Gabapentin did not decrease the 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. In a recent study, 46 lower limb amputees were randomized 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. The intensity, frequency and duration of phantom pain attacks were recorded daily in the first 30 days and after 3 and 6 months. The intensity of stump pain was also recorded and sensory testing of the stump 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 did not seem to affect outcome [36].

Opioids

Failure to provide efficient pain relief should not be accepted until opioids have been tried. In a randomized, double-blind, cross-over study with active placebo, 31 amputees received a 40-minute infusion of lidocaine (lignocaine), morphine or diphenhydramine. Compared with placebo, morphine reduced both stump and phantom pain, whereas lidocaine decreased only stump pain [37]. In another placebo-controlled, cross-over study including 12 patients, a significant reduction of phantom pain during treatment with oral morphine was found [13]. Case reports have suggested that methadone may reduce phantom pain.

NMDA receptor antagonists

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 stump and phantom pain [7]. Three other trials have examined the effect of memantine, an NMDA receptor antagonist available for oral use. In all studies, memantine was administered in a blinded, placebo-controlled, cross-over fashion to patients with established stump and phantom pain. Memantine at doses of 20 or 30 mg per day failed to have any effect on spontaneous pain, allodynia and hyperalgesia [38 -40]. Schley et al. [41] 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 4-week treatment period. Treatment with memantine resulted in a decrease of phantom pain at 4-week and 6-month follow-up, but not at 12-month follow-up. Dextromethorphan, another NMDA receptor antagonist, has also been suggested to be effective in the treatment of phantom limb pain.

Other drugs

Calcitonin significantly reduced phantom pain when used intravenously in the early postoperative phase [42]. A large number of other treatments, for example (-blockers, the oral congener of lidocaine (ligno-caine), topical application of capsaicin, intrathecal opioids, various anesthetic blocks, injection of botu-linum toxin and topiramate, have been claimed to be effective in phantom pain, but none of them has 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 pharmacologic treatments, physical therapy was the treatment modality most often used. Physical therapy involving massage, manipulation and passive movements may prevent trophic changes and vascular congestion in the stump. Other treatments, such as transcutaneous electrical nerve stimulation, acupuncture, ultrasound and hypnosis, may in some cases have a beneficial effect on stump and phantom pain. At least three studies have examined the effect of transcutaneous electrical nerve stimulation on phantom pain, but the results are not consistent. One study showed an effect of a Farabloc, a metal-threaded sock to be worn over the stump [43]. It has been suggested that visual feedback with a mirror can eliminate painful phantom limb spasms. In a larger clinical trial of 80 amputees, however, Brodie et al. [44] failed to find any significant effect of mirror treatment on phantom limb pain, sensation, and movement. Flor et al. [4] demonstrated that sensory discrimination training obtained by applying stimuli at the stump reduced pain in five upper limb amputees. 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 and other invasive treatment

Surgery on amputation neuromas and more extensive amputation previously played important roles in the treatment of stump and phantom pain. Today, stump revision is probably performed only in cases of obvious stump pathology, and in properly healed stumps 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 lesion sympath-etectomy 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 stimulation and deep brain stimulation are probably effective for the treatment of phantom limb pain. As the methods are invasive and associated with considerable costs, they should only be used for carefully selected patients.

Prevention of phantom pain

The idea of a pre-emptive analgesic effect in postamputation pain was prompted by observations that the phantom pain in some cases seemed to be similar to the pain experienced before the amputation, and that the presence of severe pain before the amputation was associated with a higher risk of postamputation phantom pain. These observations led to the theory that preamputation pain created an imprint in memorizing structures of the central nervous system, and that such an imprint could be responsible for persistent pain after amputation.

Inspired by this, Bach et al. [45] carried out the first study on the prevention of phantom pain. Twenty-five patients were randomized by birth year to either epi-dural pain treatment 72 hours before the amputation or conventional analgesics. All patients had spinal or epidural analgesia for the amputation, and both groups received conventional analgesics to treat postoperative pain. Blinding was not described. After 6 months, the incidence of phantom pain was lower among patients who had received the preoperative epidural blockade.

Jahangiri and co-workers examined the effect of perioperative epidural infusion of diamorphine, bupivacaine and clonidine on postamputation stump and phantom pain. Thirteen patients received epi-dural treatment 5-48 h preoperatively and for at least 3 days postoperatively. A control group of 11 patients received opioid analgesia on demand. All patients had general anesthesia for the amputation. The incidence of severe phantom pain was lower in the epidural group 7 days, 6 months and 1 year after amputation [46]. The study was not randomized or blinded.

Nikolajsen et al. carried out a randomized, double-blind and placebo-controlled study in which 60 patients scheduled for lower limb amputation were randomly assigned to one of two groups: a blockade group that received epidural bupivacaine and morphine before the amputation and during the operation (29 patients) and a control group that received epidural saline and oral or intramuscular morphine (31 patients). Both groups had general anesthesia for the amputation, and all patients received epidural analgesics for postoperative pain management. Patients were interviewed about preamputation pain on the day before the amputation and about stump and phantom pain after 1 week and 3, 6 and 12 months. The median duration of preoperative epidural blockade was 18 hours. After 1 week, the percentage of patients with phantom pain was 51.9% in the blockade group and 55.6% in the control group. Subsequently, the percentages were

(blockade/control): at 3 months, 82.4%/50%; at 6 months, 81.3%/55% and at 12 months, 75%/68.8%. The intensity of stump and phantom pain and the consumption of opioids were similar in the two groups at all four postoperative interviews [47].

Others have examined the effect of peri- or intraneu-ral blockade on phantom limb pain. For example, Pinzur and co-workers prospectively randomized 21 patients to continuous postoperative infusion of either bupivacaine or saline, but failed to find any difference between the two groups with regard to the incidence of phantom pain after 3 and 6 months [48].

Lambert et al. [49] compared two techniques of regional analgesia. Thirty patients were randomized to receive either epidural bupivacaine and diamorphine started 24 h before the amputation and continued 3 days postoperatively or an intraoperative perineural catheter for intra- and postoperative administration of bupivacaine. All patients had general anesthesia for the amputation. The pre-, peri- and postoperative epidural pain treatment was not superior to the intra- and postoperative perineural pain treatment in preventing phantom pain, as the incidence of phantom pain was similar in the two groups after 3 days and after 6 and 12 months.

The aim of pre-emptive treatment is to avert spinal sensitization by blocking, in advance, the cascade of intraneuronal responses that takes place after peripheral nerve injury. A true pre-emptive approach is probably not possible in patients scheduled for amputation. Many have suffered from ischemic pain for months or years and are likely to present with pre-existing neuronal hyperexcitability. It cannot be excluded that a preoperative regional blockade for a longer period would prevent phantom pain from developing. However, this would be very inconvenient from a practical point of view as the decision to amputate is often not taken until the day before.

In conclusion, regional blocks are effective in the treatment of preoperative ischemic pain and postoperative stump pain. At present, no studies of sufficient methodologic quality have provided evidence that regional blocks have any beneficial effect in preventing phantom pain. It cannot be excluded that other approaches may be effective. For example, it has been suggested that peri- and postamputation administration of NMDA receptor antagonists such as ketamine [50] and memantine [41] reduces phantom limb pain.

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