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Interactions Between Pain Medications and Illicit Street Drugs

To prevent fatal drug-drug interactions, a clinician who suspects illicit drug use should rule out their presence before prescribing pain medications, as well as other commonly known CYP 450 inhibitors or inducers.
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Fatal drug interactions between opioids and benzodiazepines, alcohol, and other sedative-hypnotic drugs have been well publicized and studied. Less publicized, however, are serious and potentially fatal drug interaction between pain medications and illicit drugs, including the ever-growing number of novel street drugs. In fact, the specific pharmacologic interactions between prescription medications commonly prescribed for pain and habitually abused illicit drugs have not been studied extensively.

When a person dies from a drug overdose, medical examiners frequently look at results from a standard detectable prescription drug(s) panel and a standard illicit substance of abuse panel. This latter panel includes commonly abused chemicals that are predetermined by specific manufacturers’ test kits. Closer scrutiny, however, could help clarify a patient’s opioid tolerance level by reviewing prescription drug history—a simple task that, in the authors’ experience, generally is not considered. But, additive or synergistic effects from untested synthetic compounds, such as cathinones (bath-salts) or JWH-type cannabinoids, increasingly are the unsung culprits causing or contributing to death.1 Medical examiners, unfortunately, don’t routinely test for these; if they do, commercially available assays have not reliably kept up with frequent chemical alterations by savvy street chemists that make it more difficult to determine causation.2,3 In the end, cardiorespiratory collapse and other findings often are attributed to opioids without considering other factors, especially undetected synthetics.4,5

Numerous peer-reviewed journals have published case reports describing adverse effects and deaths associated with illicit substances, including novel and ever-changing synthetic derivative agents of abuse.6-28 Many of these reports recommend that synthetics be included in the differential diagnosis, although they acknowledge that non-definitive immune assay (IA) urine drug tests (UDTs) frequently will be negative for prescription drugs, cannabinoids, and synthetics. The reason for these pervasive false negatives is that the current forensic use of in-office IA UDTs, which detect only classes of drugs but not individual drugs, is not definitive and not chromatography based. It would seem prudent and logical, therefore, that physicians and other clinicians validate the presence of illicit substances or the lack thereof by integrating policy standards requiring confirmatory, definitive testing by gas or liquid chromatography mass spectrometry (GC-MS or LC-MS), even when in-office testing yields a negative result.

This review highlights the potentially serious drug interactions between commonly used illicit drugs and the newer synthetic drugs of abuse when they are combined with prescription medications. Available evidence regarding such interactions, as well as the primary mechanisms of action for various illicit agents, will be reviewed.

Drug Overdoses

We used keyword and medical subject headings (MeSH) terms in PubMed, Google Scholar, DrugCite, and MedWatch databases to identify case reports of drug overdoses and interactions of prescription medications with each illegal, synthetic, or traditional drug of abuse. Keywords included drug interactions, drug overdose, as well as the prescription medication names combined with the names for each substance of abuse. All results were reviewed for relevance and included if the case report attributed the adverse reaction to the specific drug of abuse as the “primary” cause with a high degree of probability.

Available evidence, summarized in Table 1, includes street names, mechanisms of action, acute effects, health risks, and specific drugs that may potentiate the risk for serious toxicity if combined with the illicit drugs. The toxic mechanism is listed, if known, as are potential outcomes. Lastly, the table addresses limitations of standard IA UDT compared to definitive testing with GC-MS or LC-MS. The reliance on case reports, even from trustworthy sources such as poison control centers and FDA’s MedWatch, reflects the disturbing lack of data on these potentially fatal drug interactions, which are alarming considering that many of the medications discussed are among the most widely prescribed.29




The active ingredient of marijuana is delta-9-tetrahydrocannabinol (THC), a partial agonist binding to cannabinoid (Cb) type 1 receptors in the brain. THC causes various acute effects including anxiolytic and sedative effects, analgesia, and appetite stimulation.30-32 Common adverse effects include blurred vision, dizziness, xerostomia and xerophthalmia (dry mouth and eyes), hallucinations, tachycardia, hypotension, hypertension, memory loss, somnolence, and urinary retention.30

THC is metabolized via the cytochrome P (CYP) 450 system as substrates of 3A4, 2C9, and, when smoked, can induce 1A2. THC is detectable in the urine for at least 3 days after a single use and up to 27 days with chronic use.30

There are many documented interactions between marijuana and prescription, non-prescription, and illicit substances. Some drug concentrations are increased by THC (ie, lithium) and some are decreased (ie, protease inhibitors, various xanthines including theophylline). This may result in additive central nervous system (CNS) depression or sedation, especially when marijuana is used with barbiturates, anticholinergic agents, and alcohol or other CNS depressants. More serious interactions have resulted in tachycardia and delirium when cannabis is combined with tricyclic antidepressants and cyclobenzaprine, and myocardial infarction (MI) when cannabis is combined with sildenafil (Viagra).30 Combining warfarin and THC displaces protein binding and has resulted in very serious bleeding requiring hospitalization.

Synthetic Cannabinoids

Synthetic cannabinoids (Spice, K2) are full agonists at endogenous Cb type 1 and type 2 receptors.32 Numerous reports in recent years of serious adverse effects highlight the need for increased scrutiny with both marijuana and synthetic cannabinoids. Some of the cases have involved pulmonary infiltrates, acute kidney injury, MI, seizures, coma, and severe psychiatric effects, including suicidal ideation and self harm. Some evidence suggests that frequent use can precipitate psychotic symptoms in susceptible individuals perhaps unmasking an underlying psychiatric disorder.16-20,33-36

Please note that a number of synthetic cannabinoids are being studied for approval by the Food and Drug Administration. Probably the best known is Sativex, a cannabinoid that is approved in Canada for the treatment of spasticity due to multiple sclerosis. Sativex is also being studied for the treatment of cancer pain and neuropathic pain. These agents will be studied for efficacy, pharmacokinetic and pharmacodynamics effects, as well as potential drug-drug interactions prior to approval.

Last updated on: August 6, 2014
First published on: August 1, 2014