title: Pharmacologic interventions for treating phantom limb pain.
abstract: BACKGROUND
  Phantom limb pain (PLP) is pain that arises in the missing limb after amputation and can be severe, intractable and disabling. Various medications have been studied in the treatment of phantom pain. Presently there is uncertainty in the optimal pharmacologic management of PLP.
  
  
  OBJECTIVE
  This review aims to summarize the evidence of effectiveness of pharmacologic interventions in treating PLP.
  
  
  METHODS
  We searched the Cochrane Pain, Palliative and Supportive Care Review Group (PaPaS) Trials Register, the Cochrane Controlled Trials Register (CENTRAL, The Cochrane Library), MEDLINE and EMBASE up to September 2011 for randomised and quasi-randomised trials comparing pharmacologic treatment with placebo, another active treatment, or no treatment.
  
  
  METHODS
  We included randomised and quasi-randomised trials studying the effectiveness of pharmacologic interventions in patients with established PLP. The outcomes considered were change in pain intensity, function, mood, sleep, quality of life, satisfaction and adverse effects.
  
  
  METHODS
  Three review authors independently assessed the methodologic quality of the studies and extracted the data. We reported continuous and dichotomous data on change in pain intensity, function, mood/depression scores, sleep, quality of life, satisfaction for each study, where available. Because of the wide variability in the studies, we did not perform a meta-analysis for all the interventions and outcomes but we attempted to pool the results of some studies where possible. We prepared a qualitative description and narrative summary of results and described adverse effects. We assessed clinical heterogeneity by making qualitative comparisons in terms of the populations, interventions, outcomes/outcome measures and methods.
  
  
  RESULTS
  From 583 references/publications, we selected 13 studies involving 255 participants. Six groups of medications were reviewed, namely, N-methyl D-aspartate (NMDA) receptor antagonists, antidepressants, anticonvulsants, anaesthetics, opioids, and calcitonin. Ten studies were of high quality and three were of moderate quality based on both Jadad and Van Tulder criteria. Because of the wide variation (heterogeneity) in the pharmacologic interventions, outcome measures, analyses, reporting of results, duration of follow-ups and study designs, it was not possible to pool the results for most of the interventions and outcomes. Morphine (oral and intravenous) was effective in decreasing pain intensity in the short-term with reported adverse effects being constipation, sedation, tiredness, dizziness, sweating, voiding difficulty, vertigo, itching, and respiratory problems. The NMDA receptor antagonists, ketamine and dextromethorphan but not memantine, had analgesic effects. The adverse effects of ketamine were more serious and included loss of consciousness, sedation, hallucinations, hearing and position impairment, and insobriety. The results for gabapentin in terms of pain relief were conflicting but combining the results showed a trend towards benefit. Gabapentin, however, did not improve function, depression score and sleep quality. Side effects experienced were somnolence, dizziness, headache and nausea. Amitryptiline was not effective in PLP with dry mouth and dizziness as side effects based on one study. The findings for calcitonin and anaesthetics were variable. Adverse effects of calcitonin were headache, vertigo, drowsiness, nausea, vomiting, and hot and cold flushes. Most of the studies were limited by their small sample sizes.
  
  
  CONCLUSIONS
  The short- and long-term effectiveness of opioids, NMDA receptor antagonists, anticonvulsants, antidepressants, calcitonins, and anaesthetics for clinically relevant outcomes that include pain, function, mood, sleep, quality of life, satisfaction and adverse effects remains unclear. Morphine, gabapentin and ketamine demonstrate trends towards short-term analgesic efficacy. Memantine and amitriptyline were ineffective for PLP. Results, however, are to be interpreted with caution as these were based mostly on a small number of studies with limited sample sizes that varied considerably and also lacked long-term efficacy and safety outcomes. The direction of efficacy of calcitonin, anaesthetics and dextromethorphan need further clarification. Larger and more rigorous randomised controlled trials are needed to make stronger recommendations about which medications would be useful for clinical practice.
authors.affiliation: University of Melbourne-Royal Melbourne Hospital, Grattan St, Melbourne, Victoria, Australia, 3010.
authors.forename: Maria Jenelyn M
authors.initials: MJ
authors.lastname: Alviar
authors.forename: Tom
authors.initials: T
authors.lastname: Hale
authors.forename: Monalisa
authors.initials: M
authors.lastname: Dungca
mesh_terms: D000701:Analgesics, Opioid / Q000627:therapeutic use; D000777:Anesthetics / Q000627:therapeutic use; D000927:Anticonvulsants / Q000627:therapeutic use; D000928:Antidepressive Agents / Q000627:therapeutic use; D002116:Calcitonin / Q000627:therapeutic use; D006801:Humans; D010591:Phantom Limb / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
chemical_list: D000701:Analgesics, Opioid; D000777:Anesthetics; D000927:Anticonvulsants; D000928:Antidepressive Agents; D016194:Receptors, N-Methyl-D-Aspartate; D002116:Calcitonin