Dextromethorphan

Cough

Dextromethorphan and pholcodine were equally effective in 129 patients with acute, non-productive cough in a double-blind, randomized, parallel-group, multicenter trial [ ].

Pain relief

The role of dextromethorphan in acute and chronic pain control has been reviewed [ ]. There is a clear beneficial role of oral dextromethorphan (in doses of 30–90 mg) in acute pain management; it has no or few adverse effects and even reduces the need for analgesic adjuncts.

Three double-blind, crossover, randomized, placebo-controlled studies of the role of dextromethorphan in neurological pain conditions in 40 adults with diabetic neuropathy, postherpetic neuralgia, and non-specific neuropathic pain syndromes have been reviewed [ ]. Dextromethorphan dosages varied from 13.5 mg tds on alternate days to 120 mg qds. High-dose dextromethorphan significantly reduced pain in diabetic neuropathy with no effect in postherpetic neuralgia. Sedation (58%) and dizziness (25%) were the most commonly reported adverse effects.

In a randomized, placebo-controlled study in 60 patients given dextromethorphan 10, 20, or 40 mg intramuscularly before abdominal surgery, there was a dose-dependent effective postoperative analgesic effect, with lower total consumption of rescue morphine during the 3-day observation period [ ]. There were no opioid-related adverse effects in those who were given dextromethorphan 40 mg.

The effect of dextromethorphan premedication on postoperative analgesic requirements, pain scores, and adverse effects has been examined in two double-blind, randomized studies [ , ]. In the first study, 60 adults scheduled for elective upper abdominal surgery were randomly allocated to three equal groups [ ]. One group received intramuscular dextromethorphan 120 mg 30 minutes before skin incision (preincisional group); the second group received placebo (intramuscular saline) 30 minutes before skin incision and intramuscular dextromethorphan 120 mg 30 minutes before the end of surgery (postincisional group); and the third group received placebo 30 minutes before skin incision and 30 minutes before the end of surgery (control group). Preincisional intramuscular dextromethorphan 120 mg provided pre-emptive analgesia, reduced the need for postoperative analgesic supplements, and had a minimal and non-significant adverse effects profile. In the second study, oral dextromethorphan 90 mg was compared with placebo given 90 minutes preoperatively to patients undergoing laparoscopic cholecystectomy or inguinal hernioplasty under general anesthesia [ ]. Pain intensity and sedation were significantly reduced in the experimental group, with sparing of postoperative analgesics for up to 24 hours. Dextromethorphan 90 mg also abolished postoperative thermal-induced hyperalgesia and hyperpathia. No adverse effects were recorded in either group.

A randomized, double-blind, placebo-controlled study of oral dextromethorphan and PCA morphine has been performed in 66 patients undergoing knee surgery [ ]. The study was in two parts. The first was a dose escalation study in 25 postoperative patients to determine the maximum tolerated oral dose of dextromethorphan. The second involved giving less than the maximum tolerated dose divided into three increments at 8-hour intervals. The maximum tolerated dose of dextromethorphan was 750 mg. One patient, who was given 800 mg of dextromethorphan, had adverse effects, including severe slurred speech and light-headedness followed by deep sedation. In the second part of the study 66 patients were intended to receive dextromethorphan 800 mg in three doses of 400, 200, and 200 mg. The treatment group was subsequently reduced to 22 patients, compared with 34 in the placebo group, because of unexpected nausea and vomiting in five patients given dextromethorphan 400 mg. Dextromethorphan 200 mg 8-hourly caused a significant increase in nausea 2–24 hours after the first dose. One patient given dextromethorphan had mild hallucinations on one occasion only. There was an associated modest reduction in postoperative morphine consumption (29%), with no other benefits. The study failed to provide evidence that the maximum tolerated dose of dextromethorphan 200 mg 8-hourly is useful in the treatment of postoperative pain after knee surgery.

In 25 volunteers intravenous dextromethorphan 0.5 mg/kg significantly reduced areas of established hyperalgesia by 39% and prevented the development of further hyperalgesia [ ]. There was large inter-subject variability in the timing of this effect, with an average duration of 2 hours in relation to peak serum concentration. Most of the volunteers (n = 22) reported adverse events, such as mild to moderate dizziness and drowsiness. However, attention should be paid to the potential for dextromethorphan to cause phencyclidine-like effects and its potential as a drug of abuse.

In a double-blind, randomized study dextromethorphan and intrathecal morphine were used for analgesia after cesarean section under spinal anesthetic in 120 patients in six groups [ ]. The groups had differing mixtures of intrathecal morphine (0.05 mg, 0.1 mg, 0.2 mg) and dextromethorphan (60 mg) or placebo. The results suggested that the addition of dextromethorphan reduced postoperative pain and reduced the doses of morphine. The combination reduced the incidence of nausea, vomiting, and pruritus.

Dextromethorphan and pholcodine were equally effective in 129 patients with acute, non-productive cough in a double-blind, randomized, parallel-group, multicenter trial [ ].

In 15 patients with chronic neuropathic pain of traumatic origin a single oral dose of dextromethorphan (270 micrograms) produced up to 30% more reduction in analgesia than placebo [ ]. This was significant for up to 4 hours after medication. Most patients who took dextromethorphan had light-headedness and drowsiness (n = 10) and eight had visual disturbances. None of these adverse reactions was considered severe. There was individual variation in the duration of the adverse effects. Four patients were defined as poor metabolizers and four as extensive metabolizers. Even though the analgesic effect was more pronounced in the extensive metabolizers, the intensity of the adverse effects did not exhibit similar categorization and was more related to the dose.

Neuropathic pain

In a double-blind, placebo-controlled, crossover pilot study in three patients with cancer-associated postamputation phantom limb pain, oral dextromethorphan 60–90 mg bd or placebo were given for 1 week each, followed by dextromethorphan or placebo again [ ]. Dextromethorphan satisfactorily improved phantom limb pain at a dosage of 60 mg bd in two patients and 90 mg bd in the third. Even though a relatively high total dose of dextromethorphan was used, there were no adverse reactions.

There have been two randomized, placebo-controlled, double-blind trials in 19 patients with painful diabetic neuropathy and 17 with postherpetic neuralgia [ ]. In the first trial dextromethorphan was compared with memantine and/or lorazepam. Among the patients with diabetic neuropathy, dextromethorphan (median dose 400 mg/day) reduced pain intensity by a mean of 33% from baseline; memantine reduced pain by a mean of 17% and lorazepam by 16%, showing no significant difference to placebo. Among the patients with postherpetic neuralgia, dextromethorphan (median dose 400 mg/day) reduced pain intensity by a mean of 6.5%, which was not different from the effects of memantine and lorazepam. In the second trial the 10 patients with diabetic neuropathy who had responded to dextromethorphan shared a significant dose–response effect on pain intensity; the highest dose was significantly better than that of lorazepam. The median dose was 520 (range 240–920) mg/day. The adverse effects profiles were uneventful. These results confirm the long-term safety of high-dose dextromethorphan for selected patients with painful diabetic neuropathy [ ].

Non-ketotic hyperglycinemia

A review of N -methyl- d -aspartic acid (NMDA) antagonist interventions in the treatment of non-ketotic hyperglycinemia included six cases in which dextromethorphan was used [ ]. Non-ketotic hyperglycinemia is an autosomal recessive disorder in which there is failure of the glycine cleavage enzyme system, leading to impaired oxidative decarboxylation of glycine and a toxic accumulation of this amino acid. Antagonism at NMDA receptors is hypothesized to offer partial relief to the effects of this inborn error of metabolism. Of the six cases, adverse effects were described in three. Patient 1 had profound sedation in response to a dose of 7.5 mg/kg of dextromethorphan administered as a single dose when the infant was 5 days old. The same daily dosage split into three doses relieved symptoms without sedation, but doses in excess of 7.5 mg/kg resulted in somnolence, agitation, and involuntary movements. Patient 4 developed apnea, hypotonia, nystagmus, and seizures at 38 days of age and was given dextromethorphan 1 mg/kg/day at the age of 10 months, resulting in anorexia. In patient 5 an increase in dextromethorphan dosage to 10 mg/kg/day was associated with lethargy, apnea, and a return of seizure activity. Further trials are required for clarification of the use of dextromethorphan in the treatment of non-ketotic hyperglycinemia.

Parkinson’s disease

In a trial of dextromethorphan in Parkinson’s disease only one-third of the initial sample entered the double-blind, placebo-controlled phase [ ]. One-third of the sample had a reduction in the benefits of levodopa when dextromethorphan 30 mg/day was given. A further one-third withdrew because of failure to gain clinical benefit from the highest tolerated dose of dextromethorphan. Adverse effects included drowsiness, increased dystonia, increased impotence, light-headedness, sweating, and nausea.

Huntington’s disease

Of 11 patients with Huntington’s disease adverse reactions were reported in seven. These included eczematoid rash, clumsiness, dysarthria, drowsiness, and worsening rigidity [ ].