In general concurrent use of opioids and benzodiazepines results in both beneficial analgesic effects, and enhanced sedationand respiratory depression; however, in some cases benzodiazepines have antagonised respiratory depressant effects ofopioids, and, rarely, have antagonised their analgesic effects.
Clinical evidence,mechanism, importance and management
In one study, low-dose midazolam (given to achieve levels of 50 nanograms/mL) reduced dose of morphine required for postoperative analgesia in first 12 hrs (See reference number 1). However,in another study postoperative pain scores were higher in patients premedicated with oral diazepam 10 mg than with placebo, although morphine consumption did not differ (See reference number 2). Similarly, in another study, benzodiazepine antagonist flumazenil enhanced morphine analgesia in patients who had been premedicated with diazepam (See reference number 3). It is suggested that benzodiazepines antagonise analgesic effect of opioids via their effect on supraspinal GABA receptors. Why this has been shown in some studies,but not others, is unclear. Benzodiazepines and opioids are commonly used in surgical anaesthesia, and relevance of these findings to clinical practice is uncertain.
Sudden deaths in patients who abuse opioids are frequently associated with ingestion of other CNS depressants,particularly benzodiazepines.
Cases have been reported with buprenorphine,oxycodone,and tramadol(See reference number 7)taken with various benzodiazepines. It has not been established exactly why this occurs,but both pharmacodynamic and pharmacokinetic mechanisms are possible. The deleterious interaction of benzodiazepines and opioids on respiration is possibly due to central effects and/or additive actions on different neuromuscular components of respiration (See reference number 8). For buprenorphine,it is considered most likely that excessive CNS depression is solely due to combined pharmacological effects, and not to any pharmacokinetic interaction.(See reference number 9-11) See also Pharmacokinetics,below.
Intramuscular pethidine 100mg and intramuscular morphine 10mg delayed absorption of oral diazepam 10 mg. Diazepam levels were found to be lower and peak levels were not reached in 90-minute study period, when compared with peak level at 60 minutes in control group (See reference number 12). The underlying mechanism is that opioid analgesics delay gastric emptying so that rate of absorption of diazepam is reduced. The maximal effect of diazepam would be expected to be delayed in patients receiving these opioids.
Another study in healthy subjects found that dextropropoxyphene 65 mg every 6 hrs prolonged alprazolam half-life from 11
18.3 hours, and decreased clearance from 1.3 to 0.8 mL/minute per kg. The pharmacokinetics of single doses of diazepam and lorazepam were not significantly affected (See reference number 13). It would seem that dextropropoxyphene inhibits metabolism (hydroxylation) of alprazolam by liver, thereby reducing its loss from body, but has little or no effect on N-demethylation or glucuronidation of other two benzodiazepines. The clinical importance of this is uncertain, but inference to be drawn is that CNS depressant effects of alprazolam will be increased, over and above simple additive CNS depressant effects likely when other benzodiazepines and dextropropoxyphene are taken together. More study is needed.
Extended-release oxymorphone did not affect metabolism of midazolam in healthy subjects (See reference number 14). An in vitro study found that buprenorphine metabolism to norbuprenorphine was only weakly or negligibly inhibited by benzodiazepines,but midazolam had some modest effects and it was suggested that it may possibly cause some clinically relevant inhibition of buprenorphine metabolism (See reference number 15).
A 14-year-old boy with staphylococcal pneumonia secondary to influenza developed adult respiratory distress syndrome. It was decided to suppress his voluntary breathing with opioids and use assisted ventilation and he was therefore given phenoperidine and diazepam for 11 days,and later diamorphine with lorazepam. Despite receiving diamorphine 19.2mg in 24 hrs his respiratory drive was not suppressed. On day 17,despite serum morphine and lorazepam levels of 320 and 5.3 micrograms/mL,respectively, he remained conscious and his pupils were not constricted (See reference number 16). Later animal studies confirmed that lorazepam opposed respiratory depressant effects of morphine (See reference number 16).
In contrast, intravenous diazepam 150 micrograms/kg did not alter respiratory depressant effect of intravenous pethidine 1.5 mg/kg in a study in healthy subjects(See reference number 17) or in patients with chronic obstructive pulmonary disease (See reference number 18). Moreover, in setting of overdose (see (b) above), benzodiazepines might increase respiratory depressant effects of opioids.
The sedative effects of midazolam and morphine were additive in a study in patients given these drugs intravenously prior to surgery (See reference number 19). A prospective study of 80 patients undergoing elective endoscopy found that deep sedation occurred frequently (68% of patients) with pethidine and midazolam used with intent of moderate sedation (See reference number 20). Another study found that single oral doses of diazepam 10 or 20mg given to 8 buprenorphine-maintained patients increased subjective effects such as sedation and strength of drug effects,and also caused a deterioration in performance measures such as cancellation time, compared with placebo (See reference number 21).
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