Zidovudine had no effect on methadone levels in one study,butthere is one report of a patient requiring a modest increase inmethadone dose after starting zidovudine. Similarly case reportsdescribe patients requiring a modest increase in methadone doseafter starting abacavir. Methadone can increase zidovudine serum levels, and reduce levels of abacavir, stavudine, and didanosine from tablet formulation, but not enteric-coated capsule preparation. Tenofovir,and a single dose of zidovudine/lamivudine had no effect on methadone pharmacokinetics.
Eleven patients given methadone with abacavir had a 23 % increase in rate of methadone clearance but no change in half-life or renal clearance. In addition, there was a delay, and a 34 % decrease in peak concentration of abacavir, but no change in abacavir clearance or half-life (See reference number 1). Of 3 patients taking methadone who started taking abacavir,lamivudine and zidovudine, 2 required methadone dosage increases (31% and 46%, respectively). The abacavir was thought to be responsible for this effect (See reference number 2). A patient receiving methadone experienced torsades de pointes when receiving abacavir,lamivudine and zidovudine (See reference number 3).
A study in 17 subjects taking methadone found that AUC and maximum levels of didanosine tablets were 57 % and 66 % lower, respectively, when compared with 10 control subjects. Trough levels of methadone did not differ from historical controls,suggesting that didanosine had no effect on methadone pharmacokinetics (See reference number 4). A later study found that there was no reduction in AUC of didanosine given as enteric-coated capsules (See reference number 5).
A study in 17 subjects taking methadone found that AUC and maximum levels of stavudine were 23 % and 44 % lower, respectively, when compared with 10 control subjects. Trough levels of methadone did not differ from historical controls suggesting that stavudine had no effect on methadone pharmacokinetics (See reference number 4).
In a study in 13 healthy subjects receiving methadone, tenofovir 300mg daily for 2 weeks did not alter pharmacokinetics of methadone, and no symptoms of opioid toxicity or opioid withdrawal were detected (See reference number 6).
Buprenorphine. In one study, there was no difference in pharmacokinetics of oral zidovudine between patients receiving buprenorphine and control subjects (See reference number 7). Buprenorphine is not expected to cause zidovudine toxicity.
Methadone effects reduced or unaffected. A drug abuser with AIDS needed an increase in his levomethadone (R-methadone) dosage from 40 to 60mg daily,within a month of starting to take zidovudine 1 g daily (See reference number 8).
In contrast, a study found no evidence of any change in pharmacokinetics of methadone in HIV-positive patients taking methadone 14 days after they started zidovudine 200mg every 4 hours. No methadone withdrawal symptoms occurred (See reference number 9). Another study in 16 patients taking methadone found that a single-dose of a fixed combination of zidovudine 300mg with lamivudine 150mg (Combivir) had no effect on pharmacokinetics of methadone, and there was no evidence of withdrawal or toxicity (See reference number 10).
3. Zidovudine effects increased. In one study mean AUC of zidovudine was increased by 43 % by methadone, and in 4 of 9 patients it was doubled (See reference number 9). In another study, 8 HIV-positive patients starting methadone found a 29 % increase in AUC of oral zidovudine and a 41 % increase in AUC of intravenous zidovudine. Three of 8 patients stopped zidovudine because of adverse effects or haematologic toxicity (See reference number 11). Decreased zidovudine clearance in patients taking methadone is described in another report (See reference number 12).
Uncertain. It appears that methadone reduces bioavailability of didanosine, and to a lesser extent, stavudine, possibly because it delays gastric emptying. Thus, enteric-coated didanosine preparation appears not to be affected (See reference number 4,5). Conversely, methadone apparently reduces glucuronidation of zidovudine by liver, resulting in an increase in its serum levels (See reference number 13). Methadone may also reduce renal clearance of zidovudine (See reference number 11).
The increase in zidovudine levels with methadone is established, although clinical relevance is uncertain. Be alert for any increase in zidovudine adverse effects. The balance of evidence suggests that zidovudine is unlikely to reduce methadone levels, and one case reported remains unexplained, although note that some of adverse effects of zidovudine may be mistaken for opioid withdrawal effects.
The reduction in didanosine levels with methadone may be clinically relevant, and authors suggest increasing dose of tablet formulation. Monitor virological response. The enteric-coated didanosine preparation is not affected and it may therefore be worth considering using this preparation instead.
The reduction in stavudine levels and changes in abacavir peak levels with methadone are probably not clinically relevant, but again, further data are required. The reports with abacavir suggest that it would be prudent to monitor methadone dose requirements when this drug is started. Tenofovir does not appear to affect methadone levels.
Sellers E,Lam R, McDowell J, Corrigan B, Hedayetullah N, Somer G, Kirby L, Kersey K,Yuen G. The pharmacokinetics of abacavir and methadone following coadministration:CNAA1012. Intersci Conf Antimicrob Agents Chemother (1999) 39, 663.
Pardo López MA,Cuadrado Pastor JM, Pérez Hervás MP, Fernández Villalba E. Síndromede abstinencia a opiáceos tras la administración de zidovudina + lamivudina + abacavir enpacientes infectados por el virus de la inmunodeficiencia humana en tratamiento con metadona. Rev Clin Esp (2003) 203, 407–8.
Anon. Torsades de pointes with methadone. Prescrire Int (2005) 14,61–2.
Rainey PM,Friedland G, McCance-Katz EF, Andrews L, Mitchell SM, Charles C, Jatlow P.Interaction of methadone with didanosine and stavudine. J Acquir Immune Defic Syndr (2000) 24, 241–8.
Friedland G,Rainey P, Jatlow P, Andrews L, Damle B, McCance-Katz E. Pharmacokineticsof didanosine from encapsulated enteric coated bead formulation vs chewable tablet formulation in patients on chronic methadone therapy. XIV International AIDS Conference, Barcelona, 2002. Abstract TuPeB4548.
Smith PF,Kearney BP, Liaw S, Cloen D, Bullock JM, Haas CE, Yale K, Booker BM, Berenson CS, Coakley DF, Flaherty JF. Effect of tenofovir disoproxil fumarate on the pharmacokinetics and pharmacodynamics of total, R-, and S-methdone. Pharmacotherapy (2004) 24, 970–77.
McCance-Katz EF,Rainey PM, Friedland G, Kosten TR, Jatlow P. Effect of opioid dependence pharmacotherapies on zidovudine disposition. Am J Addict (2001) 10, 296–307.
Brockmeyer NH,Mertins L, Goos M. Pharmacokinetic interaction of antimicrobial agentswith levomethadon in drug-addicted AIDS patients. Klin Wochenschr (1991) 69, 16–18.
Schwartz EL,Brechbühl A-B, Kahl P, Miller MA, Selwyn PA, Friedland GH. Pharmacokinetic interactions of zidovudine and methadone in intravenous drug-using patients with HIVinfection. J Acquir Immune Defic Syndr (1992) 5, 619–26.
Rainey PM,Friedland GH, Snidow JW, McCance-Katz EF, Mitchell SM, Andrews L, LaneB, Jatlow P. The pharmacokinetics of methadone following co-administration with a lamivudine/zidovudine combination tablet in opiate-dependent subjects. Am J Addict (2002) 11, 66–
74.
McCance-Katz EF,Rainey PM, Jatlow P, Friedland G. Methadone effects on zidovudine disposition (AIDS clinical trials group 262). J Acquir Immune Defic Syndr Hum Retrovirol (1998) 18, 435–43.
Burger DM,Meenhorst PL, ten Napel CHH, Mulder JW, Neef C, Koks CHW, Bult A, Beijnen JH. Pharmacokinetic variability of zidovudine in HIV-infected individuals: subgroupanalysis and drug interactions. AIDS (1994) 8, 1683–9.
Cretton-Scott E,de Sousa G, Nicolas F, Rahmani R, Sommadossi J-P. Methadone and its metabolite N-demethyl methadone, inhibit AZT glucuronidation in vitro. Clin Pharmacol Ther (1996) 59, 168.