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Increased Overdose Risk When Combining Opioids With Other Medications

January 19, 2018

Concurrent use of opioid pain medications, benzodiazepines, antihistamines, antipsychotics, antianxiety agents, or other CNS depressants increases a patient’s risk for overdose.1

troubled man with multiple medications and opioidsAdditionally, the use of MAO inhibitors or tricyclic antidepressants with hydrocodone preparations can increase the effect of either the antidepressant or hydrocodone.2 (The patient in the following case, who was taking antidepressants and alprazolam, drank half a bottle of hydrocodone-chlorpheniramine syrup the night before his death.) Furthermore, studies indicate that depressed patients and patients with opioid use disorder are also at higher risk for drug overdose.1 Consider how the overdose in the following case might have been prevented if the treating family practice physician (FP) had followed the CDC's opioid prescribing guidelines.

For the latest CDC guiding principles and recommendations for opioid prescribing, see the 2022 Clinical Practice Guideline for Prescribing Opioids for Pain.


The FP prescribed an excessive amount of pain medications; failed to refer the patient for addiction and psychiatric treatment and failed to discover that the patient had been obtaining pain, sleep and anxiety medications from multiple physicians.

Case File

In 2007, a 25-year-old man with bronchitis, migraines, depression, bipolar disorder and past treatment for alcohol addiction started treatment with an FP. His medications included duloxetine and quetiapine for depression, nortriptyline for stress-related migraines and zolpidem for sleep. Because he could not afford to keep going to a psychiatrist, the FP agreed to prescribe his mental health medications.

In 2009, the patient had knee surgery. His surgeon prescribed hydrocodone-acetaminophen 10/300, 1 tablet every 4 to 6 hours as needed for post-surgical pain. (MME/day = 40-60.) At the patient’s request, the FP refilled the prescription every month thereafter. The patient also requested and was regularly prescribed hydrocodone-chlorpheniramine syrup, 2 doses per day for coughing related to bronchitis. (MME/day =20.) The FP was not aware that the patient was also seeing a pain management specialist, who was prescribing hydrocodone-acetaminophen 10/650 every 4-6 hours (MME/day = 40-60), zolpidem and alprazolam. All of these medications used together meant that the patient’s MME/day was 100-140.

The day before the patient died of an overdose in 2010, the FP prescribed hydrocodone-chlorpheniramine syrup. The bottle was found at his bedside. Based on what was left in the bottle, it appeared he had taken six times the recommended dosage. The cause of death was determined to be toxicity due to hydrocodone, nortriptyline, alprazolam, zolpidem and chlorpheniramine.

The patient’s family filed a wrongful death lawsuit, claiming the FP prescribed an excessive amount of pain medications; failed to refer the patient for addiction and psychiatric treatment, which he was allegedly unqualified to treat; and failed to discover that the patient had been obtaining pain, sleep and anxiety medications from multiple physicians.


The fact that the FP prescribed hydrocodone-chlorpheniramine syrup the day before the patient’s overdose made the defense of this lawsuit particularly challenging, because it appeared that the cough syrup was the major cause of the patient’s overdose. Had the FP checked the state PDMP, he most likely would have determined that the patient was getting medications from other sources. Knowing the high MME/day and high benzodiazepine daily dose probably would have prompted the FP to more carefully consider whether it was safe to regularly prescribe hydrocodone-chlorpheniramine syrup to this patient.

In his defense, the FP maintained that his prescribing was appropriate and the patient would not have died if he had taken his medications appropriately. However, experts believed the FP’s duty to appropriately treat the patient extended beyond simply writing out prescriptions. The patient was struggling with addiction and had additional mental health issues. According to experts, the FP had to take those comorbidities into consideration when he was prescribing opioids, and if he wasn’t qualified to treat the patient’s comorbidities, which the experts opined he was not, he should have referred the patient to specialists. In other words, the patient’s poor choices did not excuse the FP’s negligence.

Potential Red Flags — Patient Drug-Seeking Behavior

The following patient behaviors may indicate that your patient has an opioid addiction disorder or is diverting medications:

  • Requesting a certain drug by name
    • States alternative drug does not work
  • Seeing multiple physicians (doctor shopping)
  • Reciting textbook symptoms
  • Failing to obtain prior records
    • States previous physician closed practice
  • Showing up to appointment with pharmacy profile or test results (i.e., MRI)
  • Failing to follow through with treatment other than obtaining pain medications
  • Failing to obtain pain relief
  • Failing to comply with treatment recommendations/pain agreement
  • Calling for early refills (e.g., claiming medications were lost or stolen)
  • Testing positive for illegal drugs
  • Testing negative for prescribed pain medications (possible diversion)
  • Complaining of pain with no objective medical evidence to explain stated levels of pain
  • Paying with cash only and not using insurance

Risk Reduction Strategies

When prescribing opioids to patients with mental health and/or substance abuse disorders, extra care must be taken to avoid overdose. Consider the following recommendations, which are based primarily on the CDC guidelines:1,3,4,5

  • Obtain a complete history, including review of medical records from other physicians the patient is seeing, prior to prescribing opioids.
  • Use additional caution when prescribing opioids to patients with depression.
    • Optimize mental health treatment.
      • Refer to a behavioral health specialist when appropriate.
    • Increase the frequency of follow-ups and opioid therapy benefit/harm assessments.
  • Use additional caution when prescribing benzodiazepines, or when a patient on opioid therapy is receiving treatment for anxiety from another clinician.
    • Consider whether benefits outweigh risks of concurrent opioid and benzodiazepine use.
      • Consider consulting with a pain management specialist and/or pharmacist.
    • Suggest nonpharmacological therapies (e.g., cognitive behavioral therapy) and/or anxiety medications that are not central nervous system depressants.
    • If the patient is being prescribed benzodiazepines by another clinician, coordinate care to minimize the risks of overdose.
  • If it is available in your state, check the PDMP at opioid therapy initiation and every three months thereafter. (You can find information about signing up for a PDMP at the National Alliance for Model State Drug Laws Prescription Drug Monitoring Programs website).
    • Discuss PDMP findings with patients.
      • Confirm that the PDMP record is accurate.
      • Ensure that patients understand the overdose risks associated with high MME/day and combining medications from different sources.
      • Consider tapering to a safer dosage or discontinuing opioid therapy.
    • After advising the patient of your intention to do so, communicate with the other physicians prescribing medications that increase the risk of overdose and coordinate care.
  • Calculate the total MME/day for the opioids you are prescribing and the opioids other physicians are prescribing pursuant to information in the PDMP.
  • With the patient’s consent, conduct urine drug screening initially and thereafter as appropriate.
    • Follow standardized procedures in response to screening results indicating a patient is taking medications that you have not prescribed.
  • Assess the patient for opioid use disorder.
    • Ask patients about their drug and alcohol use.
      • Research indicates that asking, “How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?” is 100% sensitive and 73.5% specific for detecting drug use disorders in a primary healthcare setting.6
    • If the patient has an opioid use disorder, offer to or refer the patient for treatment.
  • Utilize measures to decrease overdose risk.
    • Use the lowest possible MME/day in addition to alternative pain management strategies.
    • Prescribe immediate release opioids instead of ER/LA opioids.
    • When indicated, discuss naloxone use for overdose reversal.
    • Enter into a pain medication agreement and monitor adherence. (our policyholders can obtain a sample pain medication agreement form by contacting a Risk Management Specialist.)
This content originally appeared in Claims Rx, our claims-based learning publication available in the searchable Claims Rx Directory. Many releases are available for download and eligible insureds will find instructions for obtaining CME credit for select releases.


1. Deborah Dowell, et. al. CDC Clinical Practice Guideline for Prescribing Opioids for Pain — United States, 2022. Morbidity and Mortality Weekly Report (MMWR) Recommendations and Reports 2022;71(No. RR-3):1–95. November 4, 2022. DOI: 10.15585/mmwr.rr7103a1

2. FDA. Hycodan.

3. Franklin GM. Opioids for chronic noncancer pain: A position paper of the American Academy of Neurology. Neurology 2014;83:1277-1284.

4. Manchikanti L, et al. American Society of Interventional Pain Physicians (ASIPP) Guidelines for Responsible Opioid Prescribing in Chronic Non-Cancer Pain. Pain Physician 2012;15:S1-S66.

5. Buppert C. New Standard of Care for Prescribing Opioids. 16 Apr 2015. Medscape.

6. Smith PC, et al. A Single-Question Screening Test for Drug Use in Primary Care. Arch Intern Med. 2010;170(13):1155-1160.

Filed under: Pain Management Specialist, Pain Management, Prescribing & Medication, Case Study, Physician, Opioids



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