TABLE 1.
In vivo and in vitro studies performed to examine potential drug–drug interactions between precipitant drugs and either hydrocodone, morphine, or oxycodone
| Object Drug | Precipitant Drug | Changes in Object drug pharmacokinetics/pharmacodynamics | Model system | References |
|---|---|---|---|---|
| Hydrocodone | Paroxetine | Decrease in hydromorphone AUC; minimal increase in hydrocodone AUC; inhibition of CYP2D6 | in vivo | Kapil et al., 2015 |
| Ritonavir (2D and 3D HIV treatment) | Increase in hydrocodone AUC and Cmax; decrease in norhydrocodone formation and AUC; inhibition of CYP3A4 | in vivo | Polepally et al., 2016 | |
| Ketoconazole | Norhydrocodone formation was significantly inhibited; inhibition of CYP3A4 | in vitro | Hutchinson et al., 2004 | |
| Quinidine | Hydromorphone formation was significantly inhibited; inhibition of CYP2D6 | in vitro | Hutchinson et al., 2004 | |
| Furafylline | Hydromorphone formation was significantly inhibited; inhibition of CYP2D6 | in vitro | Hutchinson et al., 2004 | |
| Troleandomycin | Norhydrocodone formation was significantly inhibited; inhibition of CYP3A4 | in vitro | Hutchinson et al., 2004 | |
| Cannabis | Decrease in hydrocodone plasma levels; increased absorption rate of hydrocodone | in vivo | Bindler et al., 2022 | |
| Clarithromycin | High hydrocodone plasma levels associated with fatality; hydromorphone not detected; CYP2D6*2A/*41 genotype present and associated with reduced function | in vivo | Madadi et al., 2010 | |
| Ibuprofen | Synergistic increase in analgesia when combined | in vivo (mice) | Kolesnikov et al., 2003 | |
| Oxycodone | Itraconazole | Increase in opioid adverse associated effects; increase in oxycodone and oxymorphone AUC; decrease in noroxycodone AUC; decrease in CYP3A4 mediated oxidation to noroxycodone | in vivo | Saari et al., 2010 |
| Voriconazole | Increase in opioid adverse associated effects; increase in oxycodone AUC; decrease in noroxycodone formation | in vivo | Hagelberg et al., 2009 | |
| Telithromycin | Increase in opioid adverse associated effects; increase in oxycodone AUC; decrease in noroxycodone formation | in vivo | Grönlund et al., 2010b | |
| Paroxetine | Decreased oxymorphone plasma levels; no significant impact on oxycodone plasma concentration; inhibition of CYP2D6 | in vivo | Grönlund et al., 2010a , 2011a | |
| Paroxetine + Itraconazole | Decrease in oxymorphone and noroxycodone plasma levels; increase in oxycodone AUC; increase in opioid adverse associated effects; inhibition of CYP3A4 and CYP2D6 | in vivo | Grönlund et al., 2010a , 2011a | |
| Grapefruit Juice | Increase in oxycodone and oxymorphone AUC; decrease in noroxycodone AUC; inhibition of CYP3A4 | in vivo | Nieminen et al., 2010a | |
| Ketoconazole | Increases in oxycodone and oxymorphone AUC; inhibition of CYP3A4 | in vivo | Samer et al., 2010a,b | |
| Quinidine | Increase in oxycodone and noroxycodone AUC; inhibition of CYP2D6 | in vivo | Samer et al., 2010a,b | |
| Rifampicin | Increase in metabolism and elimination of oxycodone; induction of CYP3A4 and CYP2D6; pharmacological effect of oxycodone attenuated | in vivo | Nieminen et al., 2009; Lee et al., 2006; Sakamoto et al., 2017 | |
| Quinidine | Decrease in formation of oxymorphone; increase in oxycodone AUC and increase in noroxycodone AUC; inhibition of CYP2D6 | in vivo | Heiskanen et al., 1998 | |
| Ketoconazole | Decrease in noroxycodone formation; increase in oxycodone and oxymorphone AUC; inhibition of CYP3A4; increase in opioid adverse associated effects | in vivo | Kummer et al., 2011 | |
| Paroxetine | Decrease in oxymorphone AUC; minimal change in oxycodone AUC; inhibition of CYP2D6 | in vivo | Kummer et al., 2011 | |
| Ritonavir or lopinavir/ritonavir | Increase in oxycodone and oxymorphone AUC; decrease in noroxycodone AUC; inhibition of CYP3A4 | in vivo | Nieminen et al., 2010b | |
| Miconazole | Increase in oxycodone AUC; decrease in oxymorphone AUC; minimal increase in noroxycodone AUC; inhibition of CYP2D6 | in vivo | Grönlund et al., 2011b | |
| Clarithromycin | Increase in oxycodone and oxymorphone AUC; decrease in noroxycodone AUC; inhibition of CYP3A4 | in vivo | Liukas et al., 2011 | |
| St. John’s Wort | Decrease in oxycodone AUC and increase in oxycodone elimination; increases in noroxycodone AUC; induction of CYP3A4 | in vivo | Nieminen et al., 2010c | |
| Aprepitant | Increase in AUC of oxycodone and oxymorphone; decrease in AUC of noroxycodone; increased Css of oxycodone and oxymorphone; decreased Css of noroxycodone; inhibition of CYP3A4 | in vivo | Fujiwara et al., 2014; Walsh et al., 2013 | |
| Paroxetine | Increase in AUC of oxycodone and noroxycodone; decrease in oxymorphone plasma levels; inhibition of CYP2D6 | in vivo | Lemberg et al., 2010 | |
| Fluoxetine and norfluoxetine | Decrease in oxymorphone formation; increase in oxycodone plasma levels; inhibition of CYP2D6 | in vitro & in vivo | Otton et al., 1993b | |
| Cyclobenzaprine | Decrease in oxymorphone and noroxycodone formation; inhibition of both CYP2D6 and CYP3A4 | in vitro | Moody et al., 2018 | |
| Orphenadrine | Decrease in oxymorphone and noroxycodone formation; inhibition of both CYP2D6 and CYP3A4 | in vitro | Moody et al., 2018 | |
| Meprobamate | Decrease in noroxycodone formation; inhibition of CYP3A4 | in vitro | Moody et al., 2018 | |
| Carisoprodol | Decrease in noroxycodone formation; inhibition of CYP3A4 | in vitro | Moody et al., 2018 | |
| Tizanidine | Decrease in oxymorphone formation; inhibition of CYP2D6 | in vitro | Moody et al., 2018 | |
| Zopiclone | Decrease in oxymorphone formation; inhibition of CYP2D6 | in vitro | Moody et al., 2018 | |
| Naloxone | Maintained oxycodone analgesia and decreased opioid induced constipation | in vivo | Clemens et al., 2011; Comelon et al., 2013; Blagden et al., 2014; Cuomo et al., 2014; Ahmedzai et al., 2015; Hesselbarth et al., 2015; Kampe et al., 2015; Lazzari et al., 2015; De Santis et al., 2016; Amato et al., 2017; Dupoiron et al., 2017 | |
| Diazepam | Additive effects of oxycodone’s analgesia was limited to a narrow dose range in the presence of diazepam | in vivo (squirrel monkey) | Leonard and Kangas, 2020 | |
| Morphine | Rifampin | Reduced AUC and Cmax of morphine and abolished analgesic effect; reduced AUC of morphine-3-glucuronide and morphine-6-glucuronide; increased levels of normorphine; inhibition of UGT2B7 and induction of CYP3A4; possible induction of P-glycoprotein | in vivo | Fromm et al., 1997 |
| Amantadine | Significant decrease in morphine-3-glucuronide plasma levels; decrease in morphine plasma clearance; increase in morphine plasma levels; inhibition of morphine to morpine-3-glucuronidation; possible competitive inhibition of tubular secretion | in vivo | Snijdelaar et al., 2004 | |
| Metoclopramide | Decrease in time to maximum drug plasma concentration with a faster onset of effects and higher level of sedation; increase in rate of absorption of morphine; further studies need to be performed to study pharmaco-kinetic and pharmacodynamic changes | in vivo | Manara et al., 1988 | |
| Methadone | Decrease in morphine-3-glucuronide and morphine-6-glucuronide formation in plasma by 2.4 and 3.5-fold, respectively; morphine plasma levels did not change; inhibition of UGT2B7 and UGT2B4 | in vivo | Gelston et al., 2012 | |
| Methadone | Significant increase in morphine plasma concentrations; decreased clearance of morphine | in vivo | Doverty et al., 2001 | |
| Clomipramine | Increased AUC of morphine; induce analgesia and potentiate morphine analgesia | in vivo (rat) | Ventafridda et al., 1990 | |
| Amitriptyline | Increased AUC of morphine; induce analgesia and potentiate morphine analgesia | in vivo (rat) | Ventafridda et al., 1990 | |
| Diclofenac | Decrease in morphine plasma levels; high morphine-6-glucuronide plasma levels were observed | in vivo | Tighe et al., 1999 | |
| Tamoxifen | Decrease in morphine-3-glucuronide and morphine-6-glucuronide formation; inhibition of UGT2B7 | in vitro | Hara et al., 2007 | |
| Tacrolimus | Decrease in morphine-3-glucuronide and morphine-6-glucuronide formation; inhibition of UGT2B7 | in vitro | Hara et al., 2007 | |
| Diclofenac | Decrease in morphine-3-glucuronide and morphine-6-glucuronide formation; inhibition of UGT2B7 | in vitro | Hara et al., 2007 | |
| Carbamazepine | Decrease in morphine-3-glucuronide and morphine-6-glucuronide formation; inhibition of UGT2B7 | in vitro | Hara et al., 2007 | |
| Imipramine | Decrease in morphine-3-glucuronide and morphine-6-glucuronide formation; inhibition of UGT2B7 | in vitro | Hara et al., 2007 | |
| Clomipramine | Decrease in morphine-3-glucuronide and morphine-6-glucuronide formation; inhibition of UGT2B7 | in vitro | Hara et al., 2007 | |
| Amitriptyline | Decrease in morphine-3-glucuronide and morphine-6-glucuronide formation; inhibition of UGT2B7 | in vitro | Hara et al., 2007 | |
| Diazepam | Decrease in morphine-3-glucuronide and morphine-6-glucuronide formation; inhibition of UGT2B7 | in vitro | Hara et al., 2007 | |
| Lorazepam | Decrease in morphine-3-glucuronide and morphine-6-glucuronide formation; inhibition of UGT2B7 | in vitro | Hara et al., 2007 | |
| Oxazepam | Decrease in morphine-3-glucuronide and morphine-6-glucuronide formation; inhibition of UGT2B7 | in vitro | Hara et al., 2007 | |
| Methadone | Decreased formation of morphine-3-glucuronide and morphine-6-glucuronide; morphine-6-glucuronide formation less pronounced as compared to morphine-3-glucuronide; inhibition of UGT2B7 by both R and S methadone | in vitro | Morrish et al., 2006 | |
| Nine traditional Japanese Medicines | Reduction in morphine-3-glucuronide formation; inhibition of UGT2B7 | in vitro | Nakagawa et al., 2009 | |
| Ketoconazole | Decrease in morphine-3-glucuronide and morphine-6-glucuronide formation; inhibition of UGT2B7 | in vitro | Takeda et al., 2006 | |
| Amitriptyline | Decreased formation of morphine-3-glucuronide; inhibition of UGT isoforms that catalyzes morphine glucuronidation to morphine-3-glucuronide | in vitro | Wahlström et al., 1994 | |
| Nortriptyline | Decreased formation of morphine-3-glucuronide; inhibition of UGT isoforms that catalyzes morphine glucuronidation to morphine-3-glucuronide | in vitro | Wahlström et al., 1994 | |
| Clomipramine | Decreased formation of morphine-3-glucuronide; inhibition of UGT isoforms that catalyzes morphine glucuronidation to morphine-3-glucuronide | in vitro | Wahlström et al., 1994 | |
| Diclofenac | Decrease in morphine-3-glucuronide and morphine-6-glucuronide formation; inhibition of UGT2B7 | in vitro | King et al., 2001 | |
| Oxazepam | Decreases in morphine-3-glucuronide and morphine-6-glucuronide formation; inhibition of UGT enzymes (unknown isoform) | in vitro | Wahlström et al., 1988 | |
| Isomenthol | Decrease in morphine-3-glucuronide and morphine-6-glucuronide formation; inhibition of UGT2B7 | in vitro | Ishii et al., 2012 | |
| Borneol | Decrease in morphine-3-glucuronide and morphine-6-glucuronide formation; inhibition of UGT2B7 | in vitro | Ishii et al., 2012 | |
| Isoborneol | Decrease in morphine-3-glucuronide and morphine-6-glucuronide formation; inhibition of UGT2B7 | in vitro | Ishii et al., 2012 | |
| Aprepitant | Decrease in morphine-6-glucuronide formation; inhibition of UGT2B7 | in vitro | House et al., 2015 | |
| Phenelzine | Development of serotonin syndrome | in vivo | Mateo-Carrasco et al., 2015 | |
| Mefenamic acid | Decrease in both morphine-3-glucuronide and morphine-6-glucuronide formation; IVIVE predicts increase of morphine AUC by 40% | in vitro | Uchaipichat et al., 2022 | |
| Naloxone | Reversal of morphine-6-glucuronide and morphine induced respiratory depression | in vivo | Olofsen et al., 2010 | |
| Alprazolam | Synergistic increase in analgesia when alprazolam and morphine are given together | in vivo (mice) | Pick, 1997 | |
| Midazolam | Potentiation of morphine induced analgesia | in vivo (rats) | Luger et al., 1994 | |
| Gabapentin | Gabapentin enhances analgesic effect of morphine | in vivo | Eckhardt et al., 2000 | |
| Ketamine | Induces antinociception in morphine tolerant rats | in vivo (rats) | Lilius et al., 2015 | |
| Metamizol | Increase in morphine plasma levels (potentially due to UGT2B7 inhibition) and increase in antinociception | in vivo (rats) | Domínguez-Ramírez et al., 2010 | |
| Haloperidol | Increased morphine analgesia | in vivo | Colclough et al., 2008 | |
| Diclofenac | Synergistic effects of morphine analgesia seen at higher doses of both morphine and diclofenac | in vivo (rats) | Fletcher et al., 1997 | |
| Propacetamol | Additive effect of morphine analgesia | in vivo (rats) | Fletcher et al., 1997 |
Css, concentration at steady state; IVIVE, in vitro to in vivo extrapolation.