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Comorbidity of mental disorders and substance use: a brief guide for the primary care clinician

6.5 Major clinical issues with anxiety disorders and opioid use

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• While opioids do not possess anxiolytic effects in the manner that benzodiazepines do, they do have the ability to enable the person to forget about the issues that may be causing them to feel anxious. An indirect short-term reduction in symptoms of anxiety may be a strong motivator for opioid use in those with anxiety disorders.
• Methadone itself has been shown to inhibit CYP3A4 which also metabolises many benzodiazepines. This has the potential to increase plasma concentrations of benzodiazepines and increase their sedative effects.
• Several deaths have been reported due to benzodiazepine use in conjunction with high dose buprenorphine and may be a result of similar metabolic interactions.
• Fluvoxamine^xxx, fluoxetine^xx, norfluoxetine^xx and paroxetine^x can inhibit buprenorphine and methadone metabolism through inhibition of the CYPs involved in their metabolism.
• Citalopram and sertraline are the least likely SSRIs to have cytochrome mediated drug interactions.
• If long-term benzodiazepine use is unable to be avoided, this should be monitored very closely.
• Acute opioid withdrawal is best managed using buprenorphine.
• If treatment of anxiety with antidepressants is required, this should involve non-sedating antidepressants such as SSRIs, taking into consideration their interaction effects.
• Longer acting maintenance pharmacotherapies such as methadone and buprenorphine potentially stabilise opioid plasma concentrations and reduce fluctuations in plasma concentration and levels of anxiety.

6.5.1 Effects of opioids on anxiety disorders

• Those with anxiety disorders are significantly more likely to use opioids than those without anxiety disorders^{(11, 25, 28, 29)}.
• While opioids do not posses anxiolytic effects in the manner that benzodiazepines do, they do have the ability to enable the person to forget about the issues that may be causing them to feel anxious. An indirect short-term reduction in symptoms of anxiety may be a strong motivator for opioid use in those with anxiety disorders.
• People with anxiety disorders report more severe opioid dependency than those without anxiety⁽²⁸⁾.
• There is some debate as to whether anxiety can potentially have an adverse impact on the effectiveness of opioid maintenance pharmacotherapy^{(238, 239)}.

6.5.2 Interactions between opioids and therapeutic agents for anxiety disorders

• Methadone itself has been shown to inhibit CYP3A4^{xx(240, 241)} which also metabolises many benzodiazepines. This has the potential to increase plasma concentrations of benzodiazepines and increase their sedative effect^{x(242, 243)}.
• Several deaths have been reported due to benzodiazepine use in conjunction with high dose buprenorphine and may be a result of similar metabolic interactions^xxx(244-246).
• Fluvoxamine^xxx, fluoxetine^xx, norfluoxetine^xx and paroxetine^x can inhibit buprenorphine and methadone metabolism through inhibition of the CYPs involved in their metabolism^(148-150). This can result in an increase in plasma opioid pharmacotherapy concentrations and potential overdose. This can be a particular issue during induction onto methadone; however, the risk may persist even after stabilisation has occurred^xxx(151-155).
• Fluvoxamine is the most potent inhibitor of methadone and buprenorphine metabolism and is the most clinically relevant. Therefore, it should be avoided^xxx(150).
• Fluoxetine and paroxetine should also be avoided due to their possible effects on methadone metabolism^xx.
• Citalopram and sertraline are the least likely SSRIs to have cytochrome-mediated drug interactions; however, due to the theoretical potential for an interaction, caution should still be used and individuals monitored closely^x(156).

6.5.3 Management approaches to comorbid anxiety disorders and opioid use

• Fluctuating plasma concentrations of short acting opioids such as heroin can exacerbate anxiety disorders due to the effects of withdrawal at times of low plasma concentration. Therefore, patients should be encouraged to reduce their use and, if possible, cease.
• Longer-acting maintenance pharmacotherapies such as methadone and buprenorphine potentially stabilise opioid plasma concentrations and reduce fluctuations in plasma concentration and levels of anxiety. However, relatively small changes in maintenance therapy concentrations can result in significant mood changes*⁽²⁴⁷⁾.
• Acute opioid withdrawal is best managed using buprenorphine****⁽²⁴⁸⁾. However, benzodiazepines can be used if there is continuing residual anxiety. Their use should be minimised due to risk of misuse⁽¹⁹⁶⁾.
• If long-term benzodiazepine use cannot be avoided:
  • This should be subject to a contract with the patient.
  • Authorities should be advised, including registration with the relevant local government health authority.
  • The seeking of additional benzodiazepines from other prescribers should be monitored (e.g. using the Authority to release personal PBS claims information to a third party form).
  • Daily or weekly dispensing of benzodiazepines in conjunction with collection of methadone or buprenorphine doses should be considered and may assist with controlling use.
• If treatment of anxiety with antidepressants is required, this should involve non-sedating antidepressants such as SSRIs, taking into consideration their interaction effects.

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