Becoming Comfortable With Discomfort: Polypharmacy for Patients With Substance Use Disorders

Psychiatric TimesVol 41, Issue 7

To expertly utilize polypharmacy, it is imperative that clinicians stay abreast of new literature, check for drug-drug interactions, and be aware of emerging trends in drug use.


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Case Study

During an intake evaluation, 32-year-old “Mark” was diagnosed with posttraumatic stress disorder, bipolar disorder, severe alcohol use disorder, severe opioid use disorder (OUD), severe tobacco use disorder, and chronic obstructive pulmonary disease. He had intensely strong nightmares from trauma and a history of 3 fentanyl overdoses. His medication regimen included :

  • Sertraline 100 mg daily
  • Prazosin 3 mg at bedtime
  • Seroquel 200 mg at bedtime
  • Acamprosate 666 mg 3 times daily
  • Buprenorphine/naloxone 24 mg daily
  • Varenicline 1 mg twice daily
  • Naloxone nasal spray PRN opioid overdose

The doctor was alarmed by the list. Mark explained it had taken 2 years to fine-tune this regimen and that he is doing much better than before. He said he was abstinent from cigarettes, alcohol, and opioids for 3 months, and he preferred to continue the same regimen. Because of his uneasiness, the doctor declined to refill the acamprosate as “it is probably not necessary anymore.” Within a week of discontinuation, Mark’s alcohol cravings worsened, he drank heavily, visited the emergency department (ED) and lost his job.

Weighing Risks and Benefits

Polypharmacy is regarded as the excessive consumption of drugs or medication, with 5 to 6 or more medications thought to be associated with an elevated risk of falls, disability, frailty, and mortality.1 In reality, the exact number of medications that is considered polypharmacy is largely variable and patient specific. It may be tempting to use polypharmacy when treating substance use disorders (SUDs) to address its enormous human, economic, and social toll.2 Yet polypharmacy may lead to adverse effects that also undermine these specific goals.

Consider the role of polypharmacy through the lens of a harm-reduction approach, which is a model more widely adopted toward successfully maintaining patient retention and reducing mortality in SUD treatment. In today’s climate, “polysubstance use is the norm.” The illicit substance market is fraught with laced drugs, unexpected substitutions, and an evolving surplus of lethal additives. Through a harm-reduction approach, almost anything is more benign than a dysfunctional life consumed by multiple substances with both known and inadvertent exposures. Thus, although not ideal, appropriate polypharmacy for certain patients could mean the difference between life and death. Like all else in harm reduction, we must carefully weigh the risks and benefits of each treatment approach, with polypharmacy being no exception. We refer to appropriate polypharmacy when there is an evidence-based rationale for each individual medication, when the regimen is effective for the patient’s symptoms and functioning, and when there is a consensus that there is no risk of excessive harm from the additive effects of the medications. This contrasts with inappropriate polypharmacy, where any 1 or more of these criteria are not met.

Treatment Plans

Treatment plans for SUDs can be challenging and vulnerable to polypharmacy regimens. For one, substance use is associated with poor psychiatric medication adherence rates due to medication adverse effects and less perceived support during recovery, likely due to stigma.3 When nonadherence is present, misattributing lack of treatment response to inadequate dosing can artificially lead to dose inflation. Similarly, cognitive deficits commonly found in this patient population may hamper the ability to recall medications and doses, leading to unnecessary addition or titration of medications. Individuals with SUDs may also use acute health care resources at higher rates. ED data from the National Hospital Ambulatory Medical Care Survey revealed that individuals with SUDs have higher rates of representation to the ED 72 hours after their initial visit and are more likely to be admitted to the hospital or intensive care unit.4 Multiple visits for acute services could place a patient at higher risk of polypharmacy.

Another consideration is diagnostic uncertainty—whether an individual’s psychosis, anxiety, and mood are substance induced or organic, leading clinicians to make medication choices for patients with and without SUDs. A patient who has substance-induced psychosis may be misdiagnosed with schizophrenia and maintained on an antipsychotic medication longer than necessary. Clinicians may feel prescribing medication is the most time-effective intervention, especially when projective identification exists (ie, when a patient’s learned helplessness from multiple failed treatment attempts leads the clinician to prescribe more medication to alleviate the clinician’s own anxiety brought on by the projected helplessness.

Half of those who experience a mental illness will experience an SUD and vice versa,5 suggesting that patients with SUDs may require more medications—both for the SUD itself and for their cooccurring psychiatric conditions. With the rising prevalence of exposure to laced and unknown drugs, use of medications with a supported evidence base and known adverse effect profile is preferable to continued hazardous use of unregulated substances with unpredictable outcomes. We also know that some medications have respectable effect sizes (buprenorphine, naltrexone, varenicline, etc), whereas others such as naloxone kits are crucial to lifesaving interventions.

Understanding SUD-associated medications is fundamental to determining the risk-benefit ratio of polypharmacy. Because effect sizes of medications used to treat SUDs can be variable, some may prefer to consider psychotherapy and group interventions preemptively before medication management. However, this may neither be feasible nor good practice. For example, a meta-analysis of in-person psychosocial SUD treatment studies revealed that individuals with stimulant use disorders tended to have higher dropout rates.6 Programs with more treatment sessions and greater average session lengths were also associated with higher treatment dropout rates. Higher psychosocial treatment dropout rates may increase the risk of return to substance use, emphasizing the importance of considering medication management early in treatment. Also, psychotherapy-based interventions may not always be available for patients. For example, among psychosocial treatment options, contingency management is a leading evidence-based approach that reinforces healthier patient behaviors. However, it can be costly and stymied by inadequate mental health provider training and moralistic ideological concerns.7 Similarly, psychotherapy programs may require complete abstinence from substances for continued treatment when patients may not be ready for complete abstinence.

In a climate where harm reduction is gaining broader acceptance, efforts to ensure patient safety is critical. Recurrence of substance use should not lead to a punitive denial of psychotherapy resources. In light of these concerns, psychopharmacologic management of SUDs is all the more critical. We must remember that we no longer prefer the term medication-assisted treatment, which implies an ancillary role of medication in recovery. The term medication for OUD is more widely embraced to highlight that medication is important in OUD recovery, with psychotherapy being ancillary but not required—not the converse. The benefits posed by medications as a form of harm reduction outweigh disadvantages such as medication adverse effects and the repercussions of failing to act, which may include overdose, accidental injury, and death. In many cases, time is of the essence. If medication offers stability, this affords the patient the ability to address their other medical issues as they progress along Maslow’s hierarchy of needs. By addressing these medical issues more promptly and making healthy lifestyle changes, the payoff may be a reduced need for more future medications.

Managing Polypharmacy

Yet, there are inevitable and significant risks to polypharmacy. Aging is associated with decreased renal elimination, decreased hepatic function, decreased total body water and lean body mass, and worsening vision and hearing.8 Physical health problems may also be prevalent and severe among populations using substances, particularly those requiring inpatient treatment. One study found that 51% of patients seeking treatment for SUDs had 2 or more major health problems.9 Among patients dependent on alcohol, the quantity of drinking prior to treatment and age were associated with physical morbidity.9 The same study found that for patients dependent on drugs, injection drug use and homelessness were associated with poorer physical health.9 For patients with greater medical comorbidities, multiple medications could be the norm, not the exception. Unfortunately, this may place patients at risk for drug-drug interactions, increased treatment costs, and even a superfluous amount of medication that could be diverted or part of an intentional or unintentional overdose.

Each clinical encounter is an opportunity for patient engagement and shared decision-making. Thus, clinicians should monitor medication regimens at each visit. Medications that are not efficacious and cause significant adverse effects should be discontinued. Risks and benefits of all medications should be periodically reviewed.

Acknowledging polypharmacy often brings about numerous transferences and countertransferences within the existing psychodynamic relationship between the patient and clinician. From the patient’s perspective, there may exist a transference that the prescriber is perhaps overtreating with medication and reducing their existence to an experiment. The opposite may also be true; the patient may perceive the clinician as uncaring and inattentive to their symptoms due to conservative prescribing patterns.

For the clinician, the countertransference may include frustration that the patient may not accept medication, or that the patient may appear “med-seeking” when asking for multiple medications. We must be mindful of these patterns and how the stigma surrounding polypharmacy may ultimately affect those with SUDs.

Monitoring can involve regular review of the state prescription drug monitoring program, routine labs, collateral information gathered from family members, and patient referrals to primary care for health conditions when indicated. Additional strategies to address polypharmacy are outlined in the Table.

 TABLE. Approaches to Managing Polypharmacy

Table. Approaches to Managing Polypharmacy

Concluding Thoughts

SUD treatment plans are a harm reduction-based opportunity for physicians to engage patients in conversations about their mental and physical health, with a careful risk-benefit analysis of polypharmacy. To do so expertly, it is imperative that we stay abreast of new literature, check for drug-drug interactions, and be aware of emerging trends in drug use.

Dr Shenoi recently completed an addiction psychiatry fellowship and is an assistant professor in the Menninger Department of Psychiatry and Behavioral Sciences at Baylor College of Medicine. Dr Li is an associate professor and addiction-boarded faculty at Harris Health System in the Menninger Department of Psychiatry and Behavioral Sciences at Baylor College of Medicine. He is also the director of the Harris Health Substance Addiction Treatment Program and an associate program director for the Baylor College of Medicine Addiction Fellowship Program.


1. Midão L, Brochado P, Almada M, et al. Frailty status and polypharmacy predict all-cause mortality in community dwelling older adults in Europe. Int J Environ Res Public Health. 2021;18(7):3580.

2. Peterson C, Li M, Xu L, et al. Assessment of annual cost of substance use disorder in US hospitals. JAMA Netw Open. 2021;4(3):e210242.

3. Magura S, Rosenblum A, Fong C. Factors associated with medication adherence among psychiatric outpatients at substance abuse risk. Open Addict J. 2011;4:58-64.

4. Zhang X, Wang N, Hou F, et al. Emergency department visits by patients with substance use disorder in the United States. West J Emerg Med. 2021;22(5):1076-1085.

5. Ross S, Peselow E. Co-occurring psychotic and addictive disorders: neurobiology and diagnosis. Clin Neuropharmacol. 2012;35(5):235-243.

6. Lappan SN, Brown AW, Hendricks PS. Dropout rates of in person psychosocial substance use disorder treatments: a systematic review and meta analysis. Addiction. 2020;115(2):201-217.

7. Petry NM. Contingency management: what it is and why psychiatrists should want to use it. Psychiatrist. 2011;35(5):161-163.

8. Drenth van Maanen AC, Wilting I, Jansen PAF. Prescribing medicines to older people—how to consider the impact of ageing on human organ and body functions. Br J Clin Pharmacol. 2020;86(10):1921-1930.

9. Keaney F, Gossop M, Dimech A, et al. Physical health problems among patients seeking treatment for substance use disorders: a comparison of drug dependent and alcohol dependent patients. J Substance Use. 2011;16(1):27-37.

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