As psychiatry and medicine expand, the general population has increasing access to medications, both over-the-counter (OTC) and prescription. Although a medication can have little to no presumed reinforcing characteristics, perhaps certain characteristics of individuals may predispose them to transition from the initiation of drug use to compulsive drug use.1 Many providers may adopt a conservative approach and prioritize the use of these various off-label medications to avoid prescribing narcotics. Although this may be a judicial approach in many cases, one must also be aware of the misuse potential of some of the most commonly prescribed non-narcotic psychiatric medications.
This article discusses several types of medications that may have potential for misuse; each have their own specific pharmacological properties, influencing the experience of a rewarding “high” during use or potentiating the effects of other substances that are taken simultaneously. It is important to recognize that certain populations may be at higher risk to misuse specific medications for various reasons.
The epidemiology of these substance use patterns is poorly understood. Only when a substance misuse becomes prominent enough for detection by drug enforcement agencies, the media, or emergency department/medical networks does a drug receive attention. Typically, case reports and case series are the first level of evidence and represent anecdotal reports. This is later followed by basic science work to elucidate use mechanisms and policy-making to counter misuse on public levels.
What Makes a Substance Addictive? Clinical Considerations
Addictive drugs can be classified by class (ie, stimulant-like, cannabinoid-like, opioid-like) or by effect (ie, hallucinogen, depressant, entactogen).2,3 Users will gravitate toward substances that provide a “high.” Initial experimental use is then followed by development of tolerance and increasing use.4 The challenge lies in identifying substances that may not be known for their “high” or pleasurable after-effects but can still promote addictive behavior.
Psychoactive substances can be described in lay terms as “addictive,” but scientific methodology classifies substances by reinforcing and rewarding properties that follow principles of operant conditioning, and that loosely translates to addictive potential. “Reinforcing” refers to the reinforcement of certain behaviors that perpetuate drug use. In animal models, these paradigms include sensitization with repeated exposures and conditioned place preference, which are subject to extinction and reinstatement.5 These mechanisms are sensitive to stress, which closely mirrors the human experience.6 Mechanisms of reinforcement had long been thought to terminally converge on the mesolimbic dopamine system.2 Dopamine release in the ventral tegmental area, nucleus accumbens, and the striatum correlates with “high” euphoric feelings; and dopaminergic transmission patterns of drug-conditioned rewards may differ from those of natural rewards such as food.7 New evidence suggests that there are dopamine-independent mechanisms that reinforce drug misuse. Some substances, including alcohol, are reinforced through the endocannabinoid system and glutamatergic transmission;8,9 this could elucidate the recent popularity of gabapentin and pre-gabalin.
Often, substances become trendy, and only after a rise in complications and deaths do we discover that they activate well-known paths in the brain. Kratom represents an example of a native plant-derived substance that was thought safe and innocuous for years but is now known to activate opioid transmission and was labeled as addictive once use became widespread.10 Even aspirin has been reported as abusable in certain contexts.11
Detection of Misuse
The detection of misuse for OTC compounds is mainly based on clinical signs because detection based off prescription review has limitations. Use of the prescription-monitoring program (PMP) to monitor narcotics can recognize a patient who is filling prescriptions under different providers, at different pharmacies, and using different forms of payment (insurance or out-of-pocket). Unfortunately, the PMP is limited to controlled medications; other substances such as quetiapine and OTC medications are not included. However, gabapentin has built momentum for inclusion on the PMP within several states, and in Kentucky it became classified as a Schedule V substance in 2017.12
Other clinical signs may be more helpful to detect misuse of nonscheduled substances. A patient asking for multiple early refills may be a red flag. Requesting rapid dose escalation, especially above therapeutic doses, could also be a clue. In these cases, seeing a patient more frequently, or providing enough medication to last only until the next appointment is an appropriate treatment boundary to reduce the risk of misuse. Avoiding “90-day” prescription refills is also advised.
Urine drug screens may, even serendipitously, reveal false-positive results secondary to the misused medication. For example, many medications may cause false positives for amphetamines, including promethazine and bupropion. There is also report of quetiapine causing false-positive results for methadone.13–15 Having an unexpected positive result can lead to a productive discussion and more intensive review of medications (both prescribed and unprescribed). Collateral information from friends and family should also not be underestimated in these situations. If there is enough suspicion of misuse, a gentle, nonjudgmental approach is key. Confronting the patient too quickly and without adequate evidence may damage the therapeutic alliance and further reduce a patient's likelihood of openly sharing his or her use patterns.
Certain medical sequelae or clinical signs can occur with overuse. For example, seizures can occur with large amounts of bupropion due to its lowering of seizure threshold, or dysrhythmias with loperamide.16 Sudden, atypical, or unexpected medical findings provide additional clues to misuse, especially if other medical etiologies are ruled out.
Promethazine is a phenothiazine derivate that is prescribed for the treatment of nausea, vomiting, and motion sickness. It is commonly included in cough syrups with codeine. The combination has been shown to potentiate the effects of the opioid and even create a different euphoric “high.”17 As a street drug, it can be mixed with other drinks including alcoholic beverages or sodas to make “lean,” “sizzurp,” or “purple drank,” which are commonly used slang words that refer to these conconctions.18 According to Lynch et al.,19 up to one-tenth of patients with chronic pain who are taking opioids have had promethazine detected in their urine, one-half of whom do not have a prescription. This suggests a high level of misuse.19 Complications of these mixtures include delirium, respiratory depression, and prolongation of the QT interval.19 Although no specific studies on the reinforcing properties of promethazine exist for humans, a previous study20 of monoamine turnover in the brains of mice shows promethazine and other H1-receptor antagonists influence dopamine turnover. Diphenhydramine, tripelennamine, and promethazine were shown to decrease dopamine turnover, possibly increasing the rewarding effect when combined with other substances, such as opioids.20
Loperamide is an OTC medication commonly used for treatment of diarrhea and is often prescribed during opioid detoxification. It works as a potent mu-opioid receptor agonist with low bioavailability and poor blood-brain barrier penetration. Most of its effect remains at the myenteric plexus to increase transit time.21 It was previously a Schedule V medication but has been available as an OTC since 1988. The medication has seen a rise in calls to poison control centers, and an increase in misuse from 2013 to 2015.16 To obtain significant effect, those who misuse loperamide may either use a CYP3A4 inhibitor such as grapefruit juice or cimetidine to decrease loperamide's metabolism, or a P-glycoprotein inhibitor like pepper or quinine to increase blood-brain barrier permeability.21 Doses up to 300 mg have been ingested with the aim of euphoria but have been linked with central nervous system depression and death.22 Cases discussing misuse of loperamide show evidence of serious cardiac effects of these high doses, including QTc interval prolongation, Torsades de pointes, ventricular dysrhythmias, and cardiac arrest.23 Its reinforcing properties are similar to that of other opioids, but at recommended doses no reinforcement is seen due to its peripheral action.
Bupropion is a dopamine and norepinephrine reuptake inhibitor used for major depressive disorder, seasonal affective disorder, and smoking cessation.24 When crushed and insufflated, bupropion will have rapid, instead of slow, onset of action at dopamine transporters (DAT). This rapid onset, especially with more than 50% of the DAT rapidly occupied, can cause euphoria and increase reward reinforcement.25 Furthermore, bupropion is a cathinone derivate, which may explain part of its misuse potential.22 Initially, bupropion was marketed as having a low misuse potential,24 but a retrospective review of intentional misuse of bupropion cited a 75% increase in misuse prevalence from 2000 to 2012.26 Inmates in correctional facilities have a high rate of drug diversion and misuse (64%–69%), and are thought to be a high-risk population for bupropion misuse.25 The most common side effects include tachycardia, seizures, agitation, hallucinations, delusions, and tremor.22
Quetiapine is not only prescribed commonly for psychotic disorders, but also for bipolar disorder as a mood stabilizer and even off-label as sleep-aid and anxiolytic.24 Quetiapine, although regarded as generally safe, can cause QT prolongation at high doses. However, a study corroborated quetiapine as the most commonly misused second-generation antipsychotic (SGA) based on the National Poison Database System query; with quetiapine-related emergency department visits increasing by 90% between 2005 and 2011, and accounting for 52% of all SGA misuse visits.27 Within the Los Angeles County Jail system, Pierre et al.28 reported that as many as 30% of patients seen provide false symptoms or exaggerate psychotic symptoms to obtain quetiapine for the purpose of sedation or anxiolytic effects. It is abused orally, through intranasal insufflation, and even through intravenous use.22,28 When administered intravenously, it has been called several street names including “Quell,” “Q”, or mixed with cocaine as a “Q-ball.”22 Misuse may be concerning for QTc prolongation.29 When examining animal models on the reinforcing properties of quetiapine, Brutcher et al.30 found that rhesus monkeys showed increased preference to low-dose cocaine once quetiapine was added. They did not find reinforcement in those who were given quetiapine alone.30 Further, a study using rats to determine the effect of antipsychotics on dopamine reward systems showed that continuous haloperidol administration increased the expression of genes associated with dopamine activity and reward-seeking behavior.31 These studies suggest that a substance use history may be a key risk to abuse of quetiapine, and antipsychotics may strengthen the reinforcing effect of other substances. Given the limited data on quetiapine abuse, we will need further studies to better guide practice.
Zolpidem is a sedative-hypnotic medication for the short-term treatment of insomnia, typically for less than 4 weeks. It has been found to be comparable to several benzodiazepines such as temazepam, with the main side effects of nausea, dizziness, and drowsiness. It has function on the GABAA receptor which shows less anxiolytic, anticonvulsant, and myorelaxant properties than benzodiazepines.32 Studies33,34 have been done showing that sedative hypnotics are reinforcing and are self-administered. Those who misuse sedative hypnotics tend to have other substance use disorders and have varying reasons for their use of the sedative.35 Reasons range from enhancing the effect of other drugs, managing the withdrawal from other substances, and even replacing an unobtainable desired drug. Although not as common as benzodiazepine addiction, its misuse is growing. In a review by Hajak et al.,36 36 cases of zolpidem dependence were reported from 1991 to 2002. Most users were taking between 8 and 120 times the daily recommended dose, with a mean dose of 400 mg per day. Most cases reported increased tolerance and withdrawal symptoms. The authors also indicate that data are limited because many countries offer zolpidem as OTC, so cases are likely underreported.36 This can be seen with reports from a southern India tertiary care facility that reviewed cases of sedative-hypnotic addiction between 2007 and 2014. At their facility, there were 950 sedative-hypnotic users, and 11.2% were taking zolpidem, making it the most commonly used “Z drug.” They corroborated that most of the patients were also addicted to other substances, with only 16.5% showing single dependence to a sedative hypnotic.37
Gabapentin was originally marketed as an anticonvulsant and later used as a medication for neuropathic pain. It is often prescribed off-label within psychiatry for treatment of alcohol use disorder and benzodiazepine use disorder, anxiety, insomnia, and other conditions. With increased prescriptions and use, more cases of misuse and abuse have appeared.22,38 Gabapentin has an overall estimated abuse rate of 40% to 65% of those with a prescription.38 In their systematic review, Smith et al.38 found a pattern that people abusing gabapentin were more likely to have a history of substance use, especially opioids, and they would take a higher dose than prescribed. Although it can be abused alone for a feeling of euphoria, relaxation, or hallucinations, it is also used in conjunction with other substances, including maintenance treatments for opioid use disorder, which include buprenorphine and methadone.38 The addition of gabapentin has been hypothesized to potentiate the effects of the opioid. The reinforcing effects are still under investigation with limited studies, but hypotheses exist that there is a direct or indirect effect on the dopamine reward system.22
Summary and Clinical Considerations
Neurobiological and environmental vulnerability factors can promote misuse of medications that are not fully associated with psychotropic effects. The clinician must remain aware of the misuse potential of a wide variety of drugs. Because these substances can be taken in a nontherapeutic fashion and with higher than intended doses, atypical adverse effects and medical complications can arise. Diagnosis of misuse relies on clinical information rather than laboratory testing, and strengthening the therapeutic rapport is essential to understand fully what the patient experiences with use and why they are using. The lack of solid scientific findings often signifies the clinician should rely on informed judgment, careful clinical evaluation, and a risk/benefit analysis when prescribing these medications to populations at-risk.
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- Pierce RC, Kumaresa V. The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse?Neurosci Biobehav Rev. 2006;30(2):215–238. doi:. doi:10.1016/j.neubiorev.2005.04.016 [CrossRef]
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- Seo J, Ko Y, Ma S, Lee B, Lee S, Jang C. Repeated restraint stress reduces the acquisition and relapse of methamphetamine-conditioned place preference but not behavioral sensitization. Brain Res Bull. 2018;139:99–104. doi:. doi:10.1016/j.brainresbull.2018.01.018 [CrossRef]
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- Di Chiara G, Bassareo V, Fenu S, et al. Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology. 2004;(suppl):227–241. doi:. doi:10.1016/j.neuropharm.2004.06.032 [CrossRef]
- Marquez J, Campos-Sandoval JA, Peñalver A, et al. Glutamate and brain glutaminases in drug addiction. Neurochem Res. 2017;42(3):846–857. doi:. doi:10.1007/s11064-016-2137-0 [CrossRef]
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- Henningfield JE, Fant RV, Wang DW. The abuse potential of kratom according the 8 factors of the controlled substances act: implications for regulation and research. Psychopharmacology. 2018;235(2):573–589. doi:. doi:10.1007/s00213-017-4813-4 [CrossRef]
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- Kentucky Board of Pharmacy. Important notice: gabapentin becomes a schedule 5 controlled substance in Kentucky. https://pharmacy.ky.gov/Documents/Gabapentin%20-%20Schedule%20V%20Controlled%20Substance.pdf. Accessed July 19, 2018.
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