Table 2.

Evidence of randomized controlled trials of pharmacological intervention.

Comparison	Intervention	Endpoint/follow-up period	Inclusions	Clinical effects
Morphine vs placebo (Randomized, cross-over, Huse et al.67)	Oral morphine sulfate (MST) titrated up to 300 mg/d, or the max. tolerable dose for 4 weeks	Outcome assessment at the end of the 4-week application period	12 patients with PLP, at least 3/10 VAS, upper extremity and lower extremity	“A significant pain reduction was found during MST but not during placebo. A clinically relevant response to MST (pain reduction of more than 50%) was evident in 42%, a partial response (pain reduction of 25%–50%) in 8% of the patients.”
Morphine vs lidocaine vs placebo (diphenhydramine) (Randomized, DB, Wu et al.148)	40 minutes IV infusion of morphine 0.2 mg/kg, 40 minutes IV infusion of lidocaine 4 mg/kg	Outcome assessment 30 minutes after end of the IV infusion	31 patients with persistent postamputation pain at least 6 months, upper extremity and lower extremity	“Compared with placebo, morphine reduced both stump and phantom pains significantly (P < 0.01). By contrast, lidocaine decreased stump (P < 0.01), but not phantom pain. The changes in sedation scores for morphine and lidocaine were not significantly different from placebo. Compared with placebo, self-reported stump pain relief was significantly greater for lidocaine (P < 0.05) and morphine (P < 0.01), whereas phantom pain relief was greater only for morphine (P < 0.01). Satisfaction scores were significantly higher for lidocaine (mean ± SD: 39.3 ± 37.8, P < 0.01) and morphine (45.9 ± 35.5, P < 0.01) when compared with placebo (9.6 ± 21.0).”
Gabapentin vs placebo (Randomized, DB, Bone et al.13)	Oral gabapentin titrated up to 2400 mg/d or the max. tolerable dose for 6-week period	Outcome assessment weekly and at the end of the 6-week application period	19 patients, pain at least 6 months, intensity at least 40/100 VAS, upper extremity and < lower extremity	“Both placebo and gabapentin treatments resulted in reduced VAS scores compared with baseline. PID was significantly greater than placebo for gabapentin therapy at the end of the treatment (3.2 ± 2.1 v 1.6 ± 0.7, P = 0.03). There were no significant differences between placebo and gabapentin therapy in terms of the number of tablets of rescue medication required, sleep interference, anxiety, depression, and daily function.”
Gabapentin vs placebo (Randomized, DB, cross-over, Smith et al.135)	Oral gabapentin titrated up to 3600 mg/d for 6-week period	Outcome assessment at the end of the 6-week application period	24 patients with PLP and residual limb pain, upper extremity and lower extremity, amputation at least 6 months; traumatic, cancer, infectious etiology	“Both placebo and gabapentin treatments resulted in reduced VAS scores compared with baseline. Pain-intensity difference was significantly greater than placebo for gabapentin therapy at the end of the treatment (3.2 ± 2.1 v 1.6 ± 0.7, P = 0.03). There were no significant differences between placebo and gabapentin therapy in terms of the number of tablets of rescue medication required, sleep interference, HAD scale, or Barthel Index. The medication was well tolerated with few reports of adverse effects”
Amitriptyline vs benztropine mesylate (Randomized, DB, Robinson et al.126)	Oral amitriptyline 10 mg/d titrated to max of 125 mg/d, oral benztropine mesylate 0.5 mg/d, each for 6 week	Outcome assessment at the end of the 6-week application period	39 patients with PLP and residual limb pain, upper-limb and lower-limb amputation, amputation at least 6 months, pain at least 3 months, pain intensity at least 2/10 NRS	Primary outcome average: pain intensity; secondary outcomes: disability, satisfaction with life, handicap; “No significant differences were found between the treatment groups in outcome variables when controlling for initial pain scores.”
Memantine vs placebo (Randomized, DB, Maier et al.92)	Oral memantine 30 mg/d; for 3 weeks	Outcome assessment at the end of the 3-week application period	36 patients with history of PLP of at least 12 months, pain intensity at least 4/10 NRS, upper extremity and lower extremity	“In both groups, PLP declined significantly in comparison with the baseline (verum: 5.1 [±2.1] to 3.8 [±2,3], placebo from 5.1 [±2.0] to 3.2 [±1.46] NRS) without a rerising of the PLP during the washout period. Mean pain relief was 47% in the memantine group (10 patients reported more than 50% relief), 40% in the placebo group (6 > 50%): NNT were 4.5 (KI: 2.1–10.6). Analysis of covariance demonstrated a significant impact only on the prior PLP intensity, but no treatment effect. Two patients have demonstrated long-term pain relief under memantine until now (16 months). The total number of slight adverse events was comparable in both groups, but the overall number of severe events was higher in the memantine group (P < 0.05).”
Memantine oral vs placebo (Randomized, DB, cross-over, Wiech et al.146)	Oral memantine up to 30 mg/d; for 4 weeks	Outcome assessment at the end of the 4-week application period	8 patients with chronic PLP, upper extremity, traumatic etiology	“In comparison to baseline and placebo, the NMDA receptor antagonist had no effect on the intensity of chronic PLP. In none of the periods were significant changes in the functional organization of SI observed.”
Memantine oral vs placebo (Randomized, DB, Schwenkreis et al.133)	Oral memantine titrated up to 30 mg/d; for 3 weeks	Outcome assessment at the end of the 3-week application period	16 patients with PLP at least 12 months, upper extremity, traumatic etiology	“Mean phantom pain was reduced in both the placebo (median – 0.9, range −3.2 to +1.2) and in the memantine group (median −2.5, range −6.3 to +0.3) in the course of the study. However, a comparison of both groups revealed no significant difference.”
Dextromethorphan vs placebo (Controlled clinical trial; DB followed by open phase, 3-period, cross-over, Ben Abraham et al.11)	Oral dextromethorphan 2 arms: 120 mg/d and 180 mg/d for 10 days	Outcome assessment at the end of the 10-day application period	10 patients with severe PLP, pain at least 1 mo, upper extremity and lower extremity, cancer etiology > traumatic, vascular	“All patients reported a >50% decrease in pain intensity, better mood, and lower sedation in each treatment phase. Four individuals reported this level of pain relief with the 60-mg and one with the 90-mg BID regimen during the double-blind phase, whereas 2 amputees benefited from the 60-mg and 3 from the 90-mg thrice-daily regimen in the open-phase trial. One reported exacerbation of pain with the 90-mg BID regimen, and 3 reported pain rebound at the 1-mo posttreatment follow-up phase. Three patients stopped all previous analgesic use during the study.”
Ketamine vs placebo (Controlled clinical trial; DB followed by open phase, 3-period, cross-over, Nikolajsen et al.108)	45 min IV infusion of ketamine 0.5 mg/kg	Outcome assessment at the end of the application	11 patients with stump and PLP, upper extremity and lower extremity, cancer etiology > traumatic, infection, reflex dystrophy, vascular	“All 11 patients responded with a decrease in the rating of stump and phantom limb pain assessed using visual analogue scale (VAS) and McGill Pain Questionnaire (MPQ). Ketamine increased pressure-pain thresholds significantly. Wind-up like pain (pain evoked by repeatedly tapping the dysaesthetic skin area) was reduced significantly by ketamine. By contrast, no effect was seen on pain evoked by repeated thermal stimuli. Side effects were observed in 9 patients.”
Ketamine vs ketamine vs calcitonin, vs combination of ketamine/calcitonin vs placebo (Randomized, DB, cross-over, Eichenberger et al.42)	1 hour IV infusion of ketamine 0.4 mg/kg, 1 hour IV infusion of calcitonin 200 IU, IV infusion 1 hour IV infusion combination of ketamine 0.4 mg/kg and calcitonin 200 IU, IV	Outcome assessment at 30 min and 60 min of infusion and 48 hours after the end of the application	20 patients (only 10 received ketamine) with PLP at least 6 months, mean pain intensity at least 3/10 VAS, upper extremity and lower extremity, vascular, traumatic, cancer, chronic pain etiology	“Ketamine, but not calcitonin, reduced phantom limb pain. The combination was not superior to ketamine alone. There was no difference in basal pain thresholds between the amputated and contralateral sides except for pressure pain. Pain thresholds were unaffected by calcitonin. The analgesic effect of the combination of calcitonin and ketamine was associated with a significant increase in electrical thresholds, but with no change in pressure and heat thresholds.”
Calcitonin vs placebo (saline) (Controlled clinical trial, cross-over, Jaeger and Maier70)	20 minutes IV infusion of 200 IU calcitonin	Outcome assessment at 24 hours after application, follow-up 7–152 days with weekly assessments	21 patients PLP in the first 7 days after amputation, upper extremity and lower extremity (only 1 upper), vascular, traumatic, cancer and infectious etiology	“In the calcitonin group, but not in the placebo group, 4 individuals remained pain-free without a second infusion. Any further treatment was performed with s-CT. One week after the first PLP treatment, 19 patients (90%) had pain relief of more than 50%, 16 (76%) were completely pain-free, and 15 (71%) never experienced PLP again. One year later, 8 out of the 13 surviving patients (62%) still had more than 75% PLP relief. After 2 y, PLP exceeded 3 on NAS in 5 individuals (42%), and the remaining 12 patients presented the same PLP as after 1 y”
Calcitonin vs ketamine (see above, Eichenberger et al.42)
Bupivacaine vs placebo (saline) (Randomized, DB, cross-over, Casale et al.20)	One contralateral myofascial injection of 1 mL of bupivacaine 2.5 mg/mL	Outcome assessment one hour after injection	8 patients with PLP at least 6 months, lower extremity, vascular, traumatic etiology	“Sixty minutes after the injection, a statistically significant greater relief of phantom limb pain was observed after using local anaesthetic than when using saline injection (P = 0.003). Bupivacaine consistently reduced/abolished the phantom sensation in 6 out of 8 patients. These effects on phantom sensation were not observed after saline injections.”
Botulinum toxin vs lidocaine and methylprednisolone (Randomized, DB, Wu et al.149)	Injection of each painful side with botulinum toxin A, 1 mL = 50 units once or injection of each painful side with combination of 0.75 mL lidocaine 1% and 0.25 mL methylprednisolone (=10 mg)	Outcome assessment monthly up to 6 months	14 patients with PLP or/and RLP, pain intensity at least 5/10 and unresponsive to conventional therapy	“Botox and lidocaine/Depomedrol injections resulted in immediate improvements of RLP (Botox: P = 0.002; lidocaine/Depomedrol: P = 0.06) and pain tolerance (Botox: P = 0.01; lidocaine/Depomedrol: P = 0.07). The treatment effect lasted for 6 months in both groups. The patients who received Botox injection had higher starting pain than those who received lidocaine/Depomedrol injection (P = 0.07). However, there were no statistical differences in RLP and pain tolerance between these 2 groups. In addition, no improvement of PLP was observed after Botox or lidocaine/methylprednisolone injection.”

BID (bis in diē): twice a day; DB double-blinded; HAD scale, Hospital Anxiety and Depression Scale; MPQ, McGill Pain Questionnaire; NAS, numeric analogue scale; NNT, number needed to treat; NMDA, N-methyl-D-aspartate; PLP, phantom limb pain; RCT, randomized controlled trial; RLP, residual limb pain; VAS, visual analogue scale.