Ritonavir decreases pethidine (meperidine) and increases norpethidine levels,which may possibly increase toxicity on long-termuse. Similarly,ritonavir and other protease inhibitors increasebuprenorphine levels. Ritonavir may increase metabolism ofmorphine, and decrease metabolism of dextropropoxyphene(CYP3A4 substrate) and tramadol or other CYP2D6 substrates(such as codeine).
One report describes 3 HIV-positive patients who experienced increased buprenorphine adverse effects (e.g. daytime sleepiness,dizziness, and reduced mental function) within about 2 days of starting to take atazanavir boosted by low-dose ritonavir. When dose of buprenorphine was reduced there was a reduction in sedative symptoms within a week (See reference number 1).
In a study in opioid-dependent patients treated with sublingual buprenorphine and naloxone, patients were given an antiretroviral (nelfinavir, lopinavir/ritonavir, or ritonavir) for 5 to 15 days to investigate effect of these drugs on QT interval. Buprenorphine/naloxone alone did not significantly alter QT interval, but when combined with an antiretroviral there was a statistically, but probably not clinically, significant increase in QT interval. The greatest increase in QTc interval was seen in patients receiving buprenorphine/naloxone with ritonavir 100mg twice daily (low booster dose) (See reference number 2).
Ritonavir 500mg twice daily for 10 days decreased AUC of a single 50mg dose of oral pethidine by 62 % and increased AUC of norpethidine by 47 % in 8 healthy subjects (See reference number 3,4). Norpethidine is pharmacologically active, and is possibly less effective an analgesic than parent compound, and more likely to cause CNS effects such as seizures.
In vitro and in vivo studies have demonstrated that ritonavir is a potent inhibitor of cytochrome P450 isoenzyme CYP3A4 and to a lesser extent CYP2D6, and may also induce glucuronidation (See reference number 4). An in vitro study suggested that buprenorphine metabolism may be inhibited by ritonavir and to a lesser extent by indinavir and saquinavir,(See reference number 5) which would be expected to lead to increased buprenorphine levels. Other opioids metabolised by CYP3A4 include dextropropoxyphene (propoxyphene),fentanyl and related drugs, (below), and methadone, . Substrates of CYP2D6 include codeine,dihydrocodeine, oxycodone, and tramadol. Morphine undergoes glucuronidation, and morphine metabolite M6G [morphine6 beta-glucuronide] is believed to contribute to analgesic effects of morphine. Buprenorphine,and to some extent, codeine also undergo glucuronidation (See reference number 6).
Most of these interactions remain theoretical, but they are consistent with way protease inhibitors and opioids interact with other drugs. The consequences of inhibition of CYP2D6 are most pronounced for codeine, and CYP2D6 inhibition will lead to decreased levels of morphine metabolite of codeine and therefore, perhaps contrary to expectation, a reduced effect. The levels of other CYP2D6 substrates dihydrocodeine,oxycodone, and tramadol would be expected to be raised, and dose reductions may be necessary. This has been suggested for tramadol (See reference number 7). It would seem prudent to monitor for adverse effects such as sedation. However,note that low-dose ritonavir (i.e. the dose used as a pharmacokinetic enhancer with other protease inhibitors) has a less potent effect on CYP2D6 and dose reductions of drugs metabolised by CYP2D6 would not generally be required if this dose of ritonavir is given concurrently (See reference number 8).
Ritonavir is a potent inhibitor of CYP3A4 and therefore UK manufacturer of ritonavir contraindicates its use with dextropropoxyphene as extremely raised dextropropoxyphene levels may occur, which would increase risk of serious respiratory depression or other serious adverse events (See reference number 4). However, US manufacturer only suggests that a dose decrease may be needed (See reference number 7).
The outcome of taking ritonavir with morphine is less clear,but it is expected that its levels will be decreased (See reference number 4,9). It would seem prudent to monitor closely to ensure morphine is effective in patients taking ritonavir. More study is needed.
It has been suggested that starting dose of buprenorphine should be halved in patients taking CYP3A4 inhibitors, such as protease inhibitors, when it is used for opioid dependence (See reference number 10). However, it has also been suggested that, since magnitude of an inhibitory effect is unknown, such drug combinations should be avoided when buprenorphine is used parenterally or sublingually as a strong analgesic (See reference number 11,12).
The manufacturers of pethidine oral preparations and injection contraindicate or advise against its use with ritonavir because of risk of norpethidine toxicity (See reference number 13,14). Long-term use of pethidine with other protease inhibitors e.g. tipranavir,which are given with low-dose ritonavir is also not recommended (See reference number 15,16).
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