Opiates and psychotropics: Pharmacokinetics for practitioners

Hydrocodone may be a viable option for patients taking 2D6 inhibitors. Hydrocodone is metabolized by 2D6 into hydromorphone, which is 7 to 33 times more potent than hydrocodone.¹⁵ Unlike codeine, 2D6 inhibition may have little effect on hydrocodone’s analgesic properties. Animal studies have shown that inhibition of the CYP analog to 2D6 does not affect analgesic response. In humans, 2D6 inhibition does not seem to affect hydrocodone’s abuse liability.¹⁶ Two case reports describe known 2D6 poor metabolizers who showed at least a partial response to hydrocodone.^15,16

Tramadol’s analgesic properties may be related to serotonin and norepinephrine reuptake inhibition. It is less potent than codeine but is metabolized via the 2D6 isoenzyme into 0-desmethyltramadol, which is up to 200 times stronger than its parent compound.¹⁷ Clinicians should be aware that tramadol’s efficacy may be decreased when coadministered with 2D6 inhibitors. In a randomized, placebo-controlled trial, paroxetine, a potent 2D6 inhibitor, was shown to lessen the analgesic effect of tramadol.¹⁸

The 3A4 site is the primary pathway for fentanyl metabolism. Agents that inhibit 3A4 could increase fentanyl plasma concentration, leading to respiratory depression.¹⁹ Examples of 3A4 inhibitors include fluoxetine and fluvoxamine.

Psychotropics may inhibit or induce P450 isoenzymes to varying degrees. For example, paroxetine and citalopram are known to inhibit 2D6 but paroxetine is a stronger inhibitor; therefore, a significant drug-drug interaction is more likely with paroxetine and a 2D6 substrate than the same substrate administered with citalopram.

Table 1

Cytochrome P450 isoenzymes inhibited and induced by psychotropics

Table 2

Cytochrome P450 isoenzymes inhibiting and inducing opiate metabolism

Other considerations

In addition to pharmacokinetic interactions, it is important to consider synergistic effects of some opiates and psychotropics. Examples include:

• additive effect on respiratory depression by benzodiazepines and opiates
• increased risk of serotonin syndrome and seizure when using tramadol with selective serotonin reuptake inhibitors or tricyclic antidepressants
• additive prolongation of the QTc interval by methadone when used with psychotropics known to prolong the QTc, such as ziprasidone.^9,17,20

Careful attention to these interactions and collaboration among providers can ensure the best outcome for our patients. In Mr. G’s case, collaboration with his internist would be in order, particularly if antidepressant choices are limited. In consultation with the psychiatrist, the internist might choose another opiate to treat Mr. G’s pain that would not interact with fluoxetine. If Mr. G and his physician have struggled to manage his pain and if he is stable on the current regimen, selecting a different antidepressant may be warranted.

Related Resources

• Indiana University School of Medicine drug interactions: cytochrome P450 drug interaction table. http://medicine.iupui.edu/clinpharm/ddis/table.asp.
• Ferrando SJ, Levenson JL, Owen JA, eds. Clinical manual of psychopharmacology in the medically ill. Arlington, VA: American Psychiatric Publishing, Inc; 2010.

Drug Brand Names

• Bupropion • Wellbutrin, Zyban
• Carbamazepine • Tegretol
• Citalopram • Celexa
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fentanyl • Duragesic, Actiq
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Hydrocodone • Lortab, Vicodin, others
• Itraconazole • Sporanox
• Meperidine • Demerol
• Methadone • Dolophine, Methadose
• Mirtazapine • Remeron
• Morphine • Avinza, Duramorph, others
• Oxycodone • OxyContin, Roxicodone
• Paroxetine • Paxil
• Risperidone • Risperdal
• Sertraline • Zoloft
• Tramadol • Ultram
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.