Drug Interactions And Opioids: What You Should Know

Given the current opioid crisis and polypharmacy concerns, this author examines the risks of potential drug-drug interactions in podiatry.

The unpleasant and subjective sensation resulting from a noxious sensory stimulus defines the phenomenon of pain. The podiatric physician is no stranger to the difficulties in achieving optimal pain therapy. Podiatric physicians must develop analgesic regimens to treat patients with acute, chronic and postoperative pain^.1

However, the topic of pain management remains a minor component of the formal education and training of residents and physicians in the United States. Misguided attitudes concerning acute and chronic pain management in addition to reservations about the legal aspects of pain management often translate into a "fear of the unknown" when it comes to narcotic prescriptions.²

On an average day in the United States, physicians dispense more than 650,000 opioid prescriptions.³ Further, the United States accounts for 4.6 percent of the world’s population yet the U.S. consumes an estimated 80 percent of the global opioid supply.⁴ There is staggering data that shows the U.S. is in the grips of an “opioid crisis.” Of the 20.5 million Americans 12 years old or older who had a substance use disorder in 2015, 2 million had a substance use disorder involving prescription pain relievers and 591,000 had a substance use disorder involving heroin.⁵

During their role of patient pain management, podiatric physicians frequently prescribe opioids. Podiatrists have an ethical obligation to prescribe responsibly and cautiously to diminish the potential for opioid diversion, and help minimize the growth of the current epidemic in opioid abuse.

The Podiatry Management 35th annual survey of 1,039 respondents reported data on the prescription habits of podiatric physicians.⁶ Survey respondents admitted to prescribing 6.1 percent prescriptions weekly. The data on the amount of oral analgesic prescriptions reveals them at the following percentages:

• acetaminophen/hydrocodone (Norco, Allergan) (13 percent)
• oxycodone/acetaminophen (Percocet, Endo Pharmaceuticals) (13 percent)
• hydrocodone (11 percent)
• tramadol (4 percent)
• acetaminophen/codeine (Tylenol 3, McNeil) (4 percent).

A notable difference between 2016 and 2017 data was a 2 percent increase in Percocet prescriptions and a 4 percent decrease in Vicodin prescriptions.⁶

The podiatrist can manage the pain of the patient while minimizing diversion potential through careful procedural techniques, non-steroidal anti-inflammatory drug (NSAID) use, and limited opioid prescriptions of appropriate quantities when necessary. In order to manage their patients' pain after invasive podiatric procedures, every practicing podiatrist must prescribe medication on occasion. Many of these analgesic medications are associated with a high likelihood of physical dependence as well as a relatively high risk of addiction.

It is critical that podiatric physicians understand the underlying issues of how these medications work and how patients can abuse them. Podiatric physicians must also exercise sound clinical judgment in identifying patients who might possibly have or will develop a physical or psychological dependence on these drugs. There is a dilemma for the podiatric physician regarding balancing patient treatment with opioids and avoiding the adverse effects contributing to the opioid crisis.

Accordingly, let us take a closer look at the prescribing of opioid analgesics to treat lower extremity pain, including keys to appropriate selection of opioid agents and what to avoid in terms of potential opioid drug-drug interactions. I will also discuss food, herbal, cigarette, alcohol and drug interactions with prescribed opioids.

Key Considerations In Prescribing Opioid Medications

Analgesic opioid therapy has been the cornerstone of pharmacologic management of acute and chronic pain. Ideally, one prescribes opioid analgesics by balancing their beneficial and adverse effects. Podiatrists and orthopedists are frequent opioid prescribers as postoperative pain is common after lower extremity surgery.

Ringwalt and colleagues accentuate this assertion by their findings centered on medical specialty opioid prescribing for non-chronic non-cancer pain.⁷ They reviewed 1.28 million filled prescriptions for an opioid analgesic over a one-year time frame. The authors concluded that general practitioner/family medicine specialists and internists were the least likely to prescribe opioids while orthopedists were the most likely to prescribe opioids. While there is currently no direct evidence, a contribution to non-medical opioid misuse is presumably a result of normal prescribing for orthopedic surgical interventions.⁷

Opioid analgesics are classified as agonist or antagonist drugs depending on their ability to bind or block opioid receptors.^1,8 Opioids each produce a wide spectrum of pharmacologic effects, including analgesia, dysphoria, euphoria, somnolence, respiratory depression, diminished gastrointestinal motility, altered circulatory dynamics, urinary retention, histamine release and physical dependence.¹ Before podiatric clinicians consider an opioid analgesic, they need to perform a complete psychosocial and physical evaluation of the patient.¹ One should prescribe opioid therapy appropriately to avoid undertreating patients with painful symptoms.

Opioid selection is based on patient-specific factors, such as age and renal function. In the setting of acute pain, some podiatric clinicians become competent in the prescribing and use of a few opioid analgesics. Although no opioid seems to be superior in relieving pain, certain products are clearly inferior because of increased risks of toxic effects.^1,9 In some circumstances, pain control is inadequate despite dosage increases.

MacPherson reviewed the concept of opioid rotation.^1,10 This method is the replacement of the current opioid regimen with another. Analgesic equivalence is the central theme when considering opioid substitution.^1,10 Mercadante defines the concept of opioid rotation as the substitution of another opioid for a previous one to obtain a more favorable response.^1,11 There are two types of opioid rotation strategies: a change in opioid product or a change in the route of administration. The emergence of morphine-equivalent tables present information related to equianalgesic doses of various opioid agents in comparison with morphine to assist clinicians with rotating opioid products. Download the table 1, “What Drugs Are Equivalent To Morphine?,” which lists opioid equianalgesic doses (see first PDF at top of page).

The last rotation strategy of opioid analgesic therapy that the podiatric physician must consider is the route of administration. Physicians have used various methods of drug delivery to treat patients in pain. The selection of the route of administration must be precise and tailored to the patent’s needs and tolerability.¹

The Institute for Clinical Systems Improvement published an acute pain assessment and appropriate opioid prescribing protocol in 2014.¹² The podiatric physician may find the following clinical points essential when prescribing opioids for acute pain.

• Providers should avoid prescribing more than three days or 20 tablets or capsules to a patient.

• Select the lowest dose and the shortest acting opioid product.

• Consider that tramadol is an atypical opioid and manage its use appropriately. 

• Never prescribe long-acting/extended release opioid for acute pain.

• Exercise caution when prescribing opioids to the elderly patient.  

• Schedule the patient to follow-up within three to five days.

• Share decision-making and review responsible use, driving, work, storage and opioid disposal with the patient. 

A Closer Look At Opioid Drug-Drug Interactions

As a drug class, opioids are associated with a narrow therapeutic index, wide variability between individuals in response and potentially life-threatening toxicity. The podiatric physician cannot be expected to memorize the staggering number of pharmaceuticals available and the equally daunting potential for drug interactions. However, prescribers should recognize that patients often come to them medicated with scores of multiple drugs acquired from different sources. 

A meticulous drug history should include an examination of the patient’s prescribed medications as well as over-the-counter drugs, herbal supplements, illicit drugs, cigarettes and alcohol consumption. One should understand the general principles of drug interactions and appreciate the major risks for interactions for the principal drug classes prescribed.

There are a number of mechanisms by which drugs interact with each other and we can divide most of them into two general categories: pharmacokinetic and pharmacodynamic interactions. With pharmacokinetic drug interactions, one drug affects the absorption, distribution, metabolism or excretion of another. When pharmacodynamic drug interactions occur, two drugs have additive or antagonistic pharmacologic effects. Either type of drug interaction can result in adverse effects in some individuals.¹³

The primary mechanisms of drug interactions include the effects of drugs on the hepatic metabolism of pharmaceuticals, effects on cytochrome P450 (CYP) enzymes or effects on glucuronidation, medication effects on the function of the drug transporter P-glycoprotein, and effects on absorption of drugs.¹⁴ Most opioid medications are metabolized by one or more of the cytochrome 450 isoenzymes, and this process typically results in the generation of multiple metabolites. In addition, other prescription medications, over-the-counter (OTC) medications, “herbals,” dietary supplements and smoking can inhibit or induce the activity of CYP450 enzymes involved in the metabolic pathways of opioid medications.

Some important preventable drug interactions are attributable to their effects on drug-metabolizing enzymes, resulting in either reduced activity of the enzyme (enzyme inhibition) or increased activity of the enzyme (enzyme induction). The major group of enzymes in the liver responsible for metabolizing drugs can be isolated in subcellular fractions termed microsomes. Cytochrome P450 is a superfamily of enzymes that are the terminal oxidases of this oxidation system. Cytochrome means colored cells. These iron-containing enzymes give the liver its red color. The name P450 comes from the observation that the enzyme absorbs a very characteristic wavelength (450 nm) of ultraviolet light when it is exposed to carbon monoxide. These enzymes are named according to families that are defined by the similarity of their amino acid sequence. The nomenclature of each cytochrome isoenzyme follows some simple rules.¹⁵ Using CYP3A4 as an example, the root of its name is CYP. Its family is noted with the number 3 and its subfamily is represented with the letter A. Its gene is denoted with the last number in the series 4.

Codeine has a high potential for drug interactions since it is metabolized by both the CYP450 2D6 and 3A isoenzymes. Codeine confers most of its analgesic effects through the formation of its metabolites. Rifampin (Rifadin, Sanofi) is a CYP450 inducer and has similar clinical consequences to CYP2D6 inhibitors when co-administered with codeine. The induction of CYP3A by rifampin will enhance codeine’s conversion to the inactive metabolite norcodeine and prevent codeine’s conversion to morphine.¹³ There are minimal pharmacokinetic changes between morphine and CYP3A inducers. While it is likely that CYP3A inhibitors are clinically inconsequential, one still needs to ensure appropriate monitoring of patients for possible toxicity.¹³

Oxycodone (OxyContin, Purdue Pharma) is metabolized in the liver by CYP3A (approximately 80 percent) to the inactive metabolite noroxycodone and to a lesser extent by CYP2D6 (less than 10 percent) to the active metabolite oxymorphone.¹³ Researchers have reported numerous interactions between oxycodone and CYP3A inhibitors and inducers. Studies have shown that rifampin markedly reduces oxycodone plasma levels.¹³ In controlled trials with healthy volunteers, the CYP3A inhibitors telithromycin (Ketek, Sanofi), itraconazole (Sporanox, Janssen), ketoconazole, miconazole, voriconazole (Vfend, Pfizer), ritonavir (Norvir, AbbVie), lopinavir (Kaletra, AbbVie) and grapefruit juice all substantially increased oxycodone exposure, generally resulting in increased opioid effects.¹³

Voriconazole can produce a fourfold increase in oxycodone plasma concentrations. Hydrocodone is a opioid prodrug and the parent compound is a relatively weak μ-receptor agonist. Hydrocodone is metabolized into its active moiety hydromorphone (Exalgo, Mallinckrodt Pharmaceuticals) by CYP2D6. Hydromorphone is unlikely to be associated with pharmacokinetic drug-drug interactions based on its metabolism because hydromorphone is metabolized by phase II metabolism.¹³ The inhibition of tramadol metabolism either by CYP2D6 or CYP3A inhibition may increase the risk of serious adverse effects to include serotonin syndrome or seizures.¹³ There have been a number of cases of serotonin syndrome following the use of serotonergic analgesics such as meperidine (Demerol, Pfizer), tramadol and tapentadol (Nucynta, Depomed) with selective serotonin reuptake inhibitors (SSRIs) or selective serotonin-norepinephrine reuptake inhibitors (SNRIs). Limited evidence suggests that fentanyl may also exhibit additive serotonergic effects with other serotonergic drugs.

For this review, download table 2, “A List Of Drug-Drug Interactions With Opioids,” which details the pharmacokinetic and pharmacodynamic changes resulting from the interaction with opioids and frequently prescribed medications by podiatric physicians (see second PDF at top of page). The table lists the opioid medications followed by the information concerning drug interactions using the terms enzyme inducers, enzyme inhibitors, and outcomes or adverse effects of the co-administration and resulting drug–drug interactions.

Enzyme inducers are substances that may increase the elimination of opioids via CYP3A4 metabolism and possibly other pathways. This results in reduced analgesic effects and possible opioid withdrawal symptoms. Enzyme inhibitors may inhibit the elimination of opioids via CYP3A4 metabolism and possibly other pathways. Researchers have reported excessive opioid effects.^1,13-15

Additionally, antimicrobials that inhibit CYP3A4 may inhibit the elimination of opioids via CYP3A4 metabolism and possibly other pathways.¹³

What The Literature Reveals About Herbal Remedies And Opioids

The use of herbal remedies has been around for centuries and their use in both Eastern and Western societies is well documented. Complementary medicines are widely available at many health food stores, pharmacies and doctors’ offices. The use of dietary supplements and herbal products in the United States has continued through 2018. Numerous herbal supplements are known to cause drug interactions, specifically with the opioid drug class that can increase the risks associated with surgery and anesthesia as well as pain control.¹⁶ The concomitant use of opioid analgesics with sedative herbs—valerian, kava and chamomile—may increase central nervous system depression and additive sedation from opioids.^13,16 The analgesic effect of opioids may be inhibited with the co-administration of ginseng.^13,16 Researchers have noted reduced plasma concentrations of oxycodone with the co-administration of St. John’s wort, leading to a decrease in analgesic effects.¹³

What About Opioid Interactions With Tobacco Products, Alcohol and Illicit Drugs?

Nearly 40 million U.S. adults still smoke cigarettes and approximately 4.7 million middle and high school students use at least one tobacco product, including e-cigarettes. Every day, more than 3,800 youth younger than 18 years smoke their first cigarette. Further, the percentage of people age 12 years and over with any illicit drug use in the past month during 2015 was an estimated 10.1 percent while the percent of people age 12 years and over with any nonmedical use of a psychotherapeutic drug in the past month during 2015 was 2.4 percent.¹⁷

Cigarette smoke, alcohol consumption and the co-ingestion of illicit drugs may interact with opioid medications through pharmacokinetic or pharmacodynamic mechanisms.^15,18 Researchers believe polycyclic aromatic hydrocarbons in tobacco smoke are responsible for the induction of cytochrome P450, CYP1A1, CYP1A2, and, possibly, CYP2E1.¹⁵ Among its various biological effects, cigarette smoke creates a pharmacokinetic reaction, resulting in drug induction and a change in drug clearance.^15,19

Alcohol is pharmacologically classified as a central nervous system depressant. Physicians prescribe narcotic pain relievers for moderate to severe pain. The combination of opioids and alcohol enhances the sedative effect of both substances, increasing the risk of death from an overdose.¹⁵

Alcohol consumption can be a contributing respiratory depression. Alcohol consumption can be a contributing factor in opioid overdose due to additive respiratory depression.¹⁵ Alcohol is converted by alcohol dehydrogenase to acetaldehyde with subsequent conversion to acetic acid and additional conversion to CO₂ and water in the Krebs cycle. Acute ethanol consumption can inhibit CYP3A4, potentiating morphine. Conversely, chronic ethanol consumption induces CYP3A4, increasing morphine metabolism and reducing analgesic effects. Benzodiazepines, which are excessively sedating, may cause severe drowsiness in the presence of alcohol.¹⁵ Fatal drug interactions between opioids and benzodiazepines, alcohol and other sedative-hypnotic drugs have been well published and studied.    

Less published, however, are serious and potentially fatal drug interactions between pain medications and illicit drugs, including the ever-growing number of novel street drugs.²⁰ In fact, the specific pharmacologic interactions between prescription medications commonly prescribed for pain and habitually abused illicit drugs have not had extensive study. There are many documented interactions between marijuana and prescription, non-prescription and illicit substances.^18,20 This may result in additive central nervous system depression or sedation, especially when a patient uses marijuana with barbiturates, anticholinergic agents, and alcohol or other central nervous system depressants, including opioids.  

Diacetylmorphine (heroin) is an opioid agonist at the mu opioid receptor. It has an extremely short half-life (five to seven minutes) and rapidly converts to morphine in the body. Heroin’s rapid onset and potency result in euphoria. The most common drug–drug interaction with heroin is with benzodiazepines, which potentiate the sedative and respiratory depressant effects of heroin. This combination is associated with more accidental overdoses than any other combination of drugs.²⁰

Kratom is one of the only known natural non-poppy or synthetically-derived opiates. Authors have reported nine cases of fatal central nervous system depression toxicity from mitragynine and O-desmethyltramadol (tramadol), which demonstrates the risk of combining kratom with less-potent opioid analgesics.^20,21 The FDA has received 44 reports of deaths associated with the use of kratom. This is an increase since the agency's November 2017 advisory, which noted 36 deaths associated with kratom.

Given that many healthcare providers overlook or are unaware of most drug-to-drug interactions, it is important that the clinician be knowledgeable about the existence of drug interactions with herbal substances, cigarette smoking, alcohol ingestion and illicit drug use to avoid a dangerous patient outcome. When patients combine opioids and social behaviors for other indications, generally by oral administration, dosages must be conservative. Download table 3, “Current Insights On Opioid Interactions With Tobacco Products, Alcohol, Illicit Drugs And Herbal Remedies,” for a summary of important drug interactions with opioid analgesics (see third PDF at top of page).

In Conclusion

In podiatric practice, drug interactions are not as voluminous as they are in medical practice. However, cross-sectional data shows that podiatric physicians do indeed prescribe a various number or opioids in their practices. Obviously, these analgesic therapies are mostly short-term in duration and the number of drug classes prescribed is of course small in comparison to primary care practices, family medicine or internal medicine specialties.

That said, podiatrists should be aware of potential opioid prescription drug interactions with other drug classes as well as social behaviors. Empowered with this information, clinicians may assist their patients to maximize pharmacologic outcomes by avoiding these reported harmful interactions.

Dr. Smith is in private practice at Shoe String Podiatry in Ormond Beach, Fla.

References

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