Few things in life are more devastating than limb amputation. This is demonstrated by the high incidence of concomitant psychopathology in limb amputees. For this reason, we screen all recent amputees for psychopathology, with particular emphasis on depression and posttraumatic stress disorder. Several studies have shown that untreated psychopathology predisposes patients to treatment failure.¹

 

When examining an amputee, emphasis should be placed on ascertaining whether the patient’s pain is truly phantom limb pain (PLP). The prevalence of chronic stump pain ranges between 5% and 22% in amputees, with some studies demonstrating an association between stump and PLP.² Stump pain may be neuropathic (eg, neuroma), nociceptive (eg, infection, heterotopic ossification) or mixed, and can be referred to the phantom limb. The distinction is clinically important since many sources of stump pain can be definitively treated with simple interventions (eg, correction of ill-fitting prostheses, neuroma injection).

 

Phantom pain is predominantly a deafferentationcondition, although peripheral mechanisms may also have a role. Membrane stabilizers and antidepressants are first-line pharmacologic agents that have shown efficacy in central pain conditions. We generally begin treatment early and aggressively with gabapentin, which was shown to be effective in a recent controlled study.³ However, since no one particular membrane stabilizer has proven optimal, the choice of agents is often determined by side effects, cost, and the likelihood of compliance. At Johns Hopkins and Walter Reed Army Medical Center, we generally use a secondary amine tricyclic antidepressant, such as nortriptyline, as our first-choice antidepressant because of their favorable side-effect profiles compared with tertiary amine drugs. In elderly patients and/or those who cannot tolerate a tricyclic drug, a serotonin norepinephrine reuptake agent can be substituted.

 

Second-line agents for central pain that we use in combination with or in lieu of anticonvulsants and antidepressants include calcitonin, N-methyl-D-aspartate (NMDA) receptor antagonists, alpha-2 agonists, and antiarrhythmics. Studies conducted at our own institutions have shown that patients who respond to an intravenous ketamine test and sympathetic blockade are more likely to experience pain relief with dextromethorphan and clonidine, respectively.

 

In responsible patients who continue to experience frequent and debilitating episodes of PLP despite appropriate treatment with adjuvant medications, we believe a trial of opioids is warranted. Sustained-release opioids are used in patients with frequent, unpredictable episodes of PLP, whereas short- or ultra-short-acting medications are reserved for breakthrough pain. In order to exploit the synergism between mu agonists and neuropathic medications, we almost always prescribe opioids in conjunction with adjuvants. Our results with spinal cord stimulation in war amputees have been disappointing thus far, which is consistent with previously published investigations.  

 

1. Fayad F, Lefevre-Colau MM, Poiraudeau S, et al. Chronicity, recurrence, and return to work in low back pain: common prognostic factors. Ann Readapt Med Phys. 2004;47:179-189.

2. Cohen SP, Christo PJ, Moroz L. Pain management in trauma patients. Am J Phys Med Rehabil. 2004;83:142-161.

3. Bone M, Critchley P, Buggy DJ. Gabapentin in postamputation phantom limb pain: a randomized, double-blind, placebo-controlled, cross-over study. Reg Anesth Pain Med. 2002;27:481-486.

N-methyl-D-aspartate (NMDA) receptor blockers are appealing because of their mechanism of action. In my experience, most of the commercially available drugs with this property do not exhibit much in the way of clinical efficacy for pain. I have tried memantine*, amantadine*, propoxyphene, dextromethorphan*, methadone, and ketamine*. Of these, only methadone and ketamine have been effective pain medications for wind-up pain, in my own clinical experience. Methadone is obviously a powerful analgesic opioid, as well as a moderate NMDA receptor blocker. Ketamine is a potent NMDA receptor blocker. There are no good, long-term studies of the effects of ketamine, but we have used it with good effect for the last 8 years in many patients. In clinical practice, we mostly use ketamine in a transdermal vehicle, such as organogel or lipoderm. We have used it less frequently in a compounded oral formulation, but I would not recommend using this form of administration outside of a pain specialty practice. There are anesthesiologists who administered pulse intravenous (IV) ketamine or anesthetic IV ketamine treatments for severely intractable pain disorders, but again, this needs to be done in an anesthesia suite under the careful supervision of an experienced anesthesiologist. The only on-label use of ketamine is as a general anesthetic.

 

 

*Not FDA approved for this indication.

Technically, you can switch a patient from 600 mg of gabapentin to 50 mg of pregabalin, but I rarely do that. I’ll usually cut back on the gabapentin dose by eliminating a midday 600-mg dose of gabapentin and replacing it with a 50-mg dose of Lyrica. I’ll do that for a week and then do the same thing with the evening and morning doses. Sometimes I leave a patient on a combination of gabapentin and Lyrica if the patient has more cognitive deficits on Lyrica alone and gets some benefit from gabapentin. Although it is always an option to take the patient off the other antiepilepsy (AED) drug first, there is no reason that pregabalin can't be substituted for another AED while titrating down the original medication.

There is no on-label use of ketamine for pain; its only on-label use is as a dissociative anesthetic. That being said, we use it frequently as a 10% solution in pluronic lecithin organogel (PLO), a transdermal cream. A compounding pharmacist has to make the compound, and we usually have the patient rub the ketamine in PLO over the area of injury. Occasionally, we have the patient try it over the area of referred or perceived pain, but when we know the peripheral stimulus site, we have them use it there. Ketamine has sodium channel blocking properties locally and we see a fast, robust, but usually short-lived, effect from this. It has systemic N-methyl-D- aspartate receptor blocking properties that are longer lasting and potentially decrease wind-up pain and opioid tolerance.

My answer to this question is to start by confirming that the patient does in fact have the condition, complex regional pain syndrome type 1 (CRPS 1), a condition for which you have used the term “reflex sympathetic dystrophy.” There are published established diagnostic criteria for CRPS types 1 and 2.¹ Other possible sources of the patient’s chronic neuropathic pain must have been considered and ruled out following an appropriate diagnostic evaluation. The importance of this cannot be overstated, as treating a syndrome with a more directly treatable cause for the patient’s pain may result in a better outcome. In other words, the diagnosis of CRPS 1 is a diagnosis of exclusion.

 

Let us assume that this is her actual diagnosis. An important step is to determine if there are coexistent musculoskeletal aspects to her pain syndrome. Many patients with CRPS 1 have coexisting myofascial pain/painful muscle spasm and in addition, many patients with post- laminectomy pain have similar complaints. Evaluation questions to consider include:

The patient’s answer to the question regarding other treatment options needs to be considered in the context of her other answers to the above questions.

 

If during your evaluation you come to believe that myofascial pain/dysfunction has an important role in the patient’s chronic pain, consider physical therapy. If this has been unsuccessful, consider the use of trigger point injection therapy and possibly botulinum toxin injection therapy. There is published evidence for the role of botulinum toxin in the treatment of this kind of chronic low back pain.² Also consider the use of other injection therapies, depending on the presence of radicular or nonradicular complaints/findings, her previous response to similar therapy, and, of course, the results of her neuroimaging and/or electrophysiologic tests. Perhaps the stimulator leads need to be repositioned, the stimulator needs to be reprogrammed, and/or different types of leads need to be utilized. Some patients may also require intrathecal analgesic treatment.

 

From a pharmacotherapeutic viewpoint, numerous options exist. Many evidence-based agents are available for the management of neuropathic pain syndromes. Although those that are FDA-approved are indicated in only three conditions—trigeminal neuralgia, postherpetic neuralgia, and painful diabetic neuropathy—it may certainly be worthwhile to consider using them in a patient with CRPS 1, a presumed neuropathic pain state. Such agents include gabapentin*, pregabalin*, lidocaine patch 5%*, duloxetine*, tramadol*, tricyclic antidepressants*, and opioids*. If your current treatment focus is on pharmacotherapy, keep in mind that a single agent may not provide sufficient relief. A recently published study found for example that the combination of gabapentin and morphine for the treatment of patients with different neuropathic pain states was superior to either medication alone.³ In addition, lower doses of each agent were required (on average) than when used alone. This directs you to the potential need for multidrug therapy, as well as integrated treatment combining both interventional and noninterventional approaches. Regardless of the options chosen, careful and frequent follow-up assessing for benefit and acceptable side effects (if any) is part of the treatment, as well.

 

* Not FDA-approved for this indication.

 

References

1. Galer BS, Bruehl S, Harden RN. IASP diagnostic criteria for complex regional pain syndrome: a preliminary empirical validation study. International Association for the Study of Pain. Clin J Pain. 1998;14:48-54.

2. Ney JP, Difazio M, Sichani A, Monacci W, Foster L, Jabbari B. Treatment of chronic low back pain with successive injections of botulinum toxin over 6 months: a prospective trial of 60 patients. Clin J Pain. 2006;22:363-369.

3. Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005;352:1324-1334.