- StatPearls: Prescription of Controlled Substances: Benefits and Risks [BOOK]
- BOOKStatPearls Publishing: Treasure Island (FL)
- One of the single most difficult challenges for any prescriber is to distinguish between the legitimate prescription of controlled substances versus the prescription potentially used for illegitimate…
One of the single most difficult challenges for any prescriber is to distinguish between the legitimate prescription of controlled substances versus the prescription potentially used for illegitimate purposes. To discern the difference prescribers need to understand the signs, symptoms, and treatment of acute and chronic pain as well as the signs and symptoms of patients using controlled substances for non-legitimate purposes. A common reason people seek the care of medical professionals is pain relief. While many categories of pain medications are available, opioid analgesics are FDA-approved for moderate to severe pain. As such, they are a common choice for patients with acute, cancer-related, neurologic, and end-of-life pain. The prescribing of opioid analgesics for chronic pain is controversial and fraught with inconclusive standards. In the 1990s, due to the chronic failure of health professionals to undertreat severe pain, opioid analgesic prescribing was expanded. Unfortunately, this led to increased overuse, diversion of drugs, opioid use disorder, and overdose. The "Catch-22" seems to be either health professionals undertreat, and there is needless suffering, or they overtreat, with a potential to cause adverse effects like increased opioid analgesic use disorder and potential overdose. The prescription of opioid analgesics peaked in 2011, since then both prescribing and overdose has been declining; yet as a society, in both the lay and scientific literature, there are grave concerns that we are still in the middle of an opioid crisis. Perhaps the biggest challenge of caring for patients with pain is that individuals have different levels of tolerance and require variable opioid doses to obtain adequate pain relief. Patients may have a range of behavioral, cultural, emotional, and psychologic responses to pain versus a substance use disorder; often it is challenging to tell the difference. All health professionals engaged in pain management need an understanding of the treatment recommendations and safety concerns in prescribing opioid analgesics. Appropriate opioid prescribing requires a thorough patient assessment, short and long-term treatment planning, close follow-up, and continued monitoring. All providers need to be aware of not only appropriate patient assessment and treatment planning but also the possibility of use disorder, diversion, and potentially dangerous behavioral responses to controlled substances, e.g., opioid analgesics differ from pseudo-addiction and physical dependence. It is unfortunately clear that many clinicians know little about opioid use disorder; they do not understand it is a disease, and many believe opioid dependence is the same as opioid use disorder. Lack of a clear understanding results in clinicians confusing a chronic non-use disorder pain patient from the one who is misusing their prescribed opioid. Lack of training and educational deficits often interferes with the appropriate prescription of opioid analgesic agents. To prevent misuse of controlled substances, providers that prescribe controlled substances should learn prescribing practices that minimize or prevent adverse consequences. Definitions Addiction - according to the American Society of Addiction Medicine (ASAM) - "Addiction is a primary, chronic disease of brain reward, motivation, memory, and related circuitry. Dysfunction in these circuits leads to characteristic biologic, psychologic, social, and spiritual manifestations. This is reflected in an individual pathologically pursuing reward or relief by substance use and other behaviors." Addiction is now termed "use disorder," and is characterized by an inability to consistently abstain, craving, impairment in behavioral control, diminished ability to recognize significant problems with one's behaviors and interpersonal relationships, and a dysfunctional emotional response. Like other chronic diseases, use disorder often involves cycles of relapse and remission. Without treatment or engagement in recovery activities, use disorder is progressive and can result in disability or premature death." Appropriate opioid prescribing - providing pain control while minimizing use disorder or risk of same, and toxicity; and implementing safeguards to reduce drug diversion. Inappropriate opioid analgesic prescribing - non-, inadequate, excessive, or continued prescribing despite evidence of the lack of effective opioid treatment. Controlled substances - drugs or medications that possess the potential for being misused and are considered to be substances that have a substantially high risk of resulting in substance use disorder. Narcotics - comes from the Greek word for stupor and originally referred to drugs that dulled the senses and relieved pain, e.g., morphine. Also, narcotics were any drug that induced sleep. A more precise term for this class of drugs, with less uncertainty regarding its meaning, is opioid analgesics. Please note that the Drug Enforcement Administration (DEA, USA) uses the term narcotic to refer to drugs that are opioid analgesics. Five Characteristics of Addiction/Use Disorder (ASAM): 1. Craving for drug or reward. 2. Diminished recognition of significant problems in one's behavior. 3. Dysfunctional emotional response. 4. Impairment in behavioral control. 5. Inability to consistently abstain Drug Schedules of Controlled Substances All providers should be familiar with the guidelines and laws for each schedule which have as their basis the purpose of the drug and the risk of use disorder. In the United States, controlled substances are under strict regulation by both federal and state laws which guide their manufacture and distribution. Controlled substances have a high risk of resulting in an addiction and substance use disorder. As the schedules decrease, I-V, the drugs listed within each category have a lower potential to cause a substance use or addiction disorder. Controlled Substance Act In the United States, the Comprehensive Drug Abuse Prevention and Control Act was passed in 1970, and it included the Controlled Substance Act. The Controlled Substance Act covers drug: Classification and regulation, according to their content and purpose. Manufacturing. Distribution. Exportation and sale. The Controlled Substance Act established five drug schedules and classified them to control their manufacture and distribution. Part of regulation requires providers that prescribe scheduled drugs and pharmacists that fill them to obtain a license from the Drug Enforcement Administration. Health professionals licenses include specific license numbers allowing controlled substance prescriptions to be tracked and linked to a particular provider or distributor. Of the five schedules, each has parameters based on their medical value, the risk of addiction, and ability to cause harm. The schedules range from schedule I (most potential for addiction and use disorder) to schedule V (least potential for addiction/use disorder). Schedule I: Schedule I drugs possess the highest potential for use disorder and misuse. They have no medical use and are illicit or “street” drugs. Examples of Schedule I drugs include heroin, lysergic acid diethylamide, mescaline, methylenedioxymethamphetamine (MDMA), and methaqualone. Marijuana, which is legal in some states, is still classified as a Schedule I drug at the federal level as of this writing. Schedule II : Schedule II drugs have a reduced potential for use disorders than I. They are high risk for both physical and psychological dependence. They have a high capacity for both use disorder and misuse. They are typically prescribed to treat severe pain, anxiety, insomnia, and ADHD. Examples of Schedule II substances include fentanyl, hydromorphone, meperidine, methadone, morphine, oxycodone, fentanyl, dextroamphetamine, methylphenidate, methamphetamine, pentobarbital, and secobarbital. They previously had to be prescribed only via paper prescription, but now are permitted to be electronically transmitted. (Electronic Prescribing of Controlled Substances or EPCS). No refills are allowed. Schedule II drugs have the tightest regulations when compared to other prescription drugs. Schedule III : Schedule III drugs are those with a lower misuse potential than I and II. Drugs in this category may cause physical dependence but more commonly lead to psychological dependence. Medications in this category are often used for pain control, or anesthesia or appetite suppression. Examples of Schedule III substances include benzphetamine, ketamine, phendimetrazine, and anabolic steroids. Opioid analgesics in this schedule include products containing not more than 90 milligrams of codeine per dosage unit, and buprenorphine. Schedule III drugs are prescribable verbally over the phone, with a paper prescription, or via EPCS. Within a six-month time frame, refill requirements are such that the drug can only have five refills. Schedule IV: Schedule IV drugs have an even lower misuse potential than I, II, or III. They have a limited risk of physical or psychological dependence. Examples of Schedule IV substances include: alprazolam, carisoprodol, clonazepam, clorazepate, diazepam, lorazepam, midazolam, temazepam, tramadol, and triazolam. Drugs in this class may be utilized for pain control as long as the provider deems the drug to be medically necessary and that the patient would benefit. Schedule IV drugs are prescribable verbally over the phone, with a paper prescription, or via EPCS. Refills are permitted up to five times in a six-month timeframe from the issuance date. Schedule V: Schedule V drugs are the least likely controlled substances to be misused. They result in very limited physical dependence or psychological dependence. Examples include cough medicines with codeine, antidiarrheal medications that contain atropine/diphenoxylate, pregabalin, and ezogabine. Schedule V drugs despite their low abuse potential, still need to be managed appropriately and administered with care. When they contain codeine, it must have less than 200 mg of codeine per 100 mL. Partial prescription fills cannot occur more than six months after the date of issue. When a partial fill occurs, it is treated in the same manner and with the same rules as a refill of the drug. Drug Use Disorder, Abuse, and Misuse Use disorder of a drug differs from abuse and misuse of a drug. The drugs taken may be illicit street or stolen drugs or obtained via a legal prescription. Misusing a drug usually involves taking the drug in a harmful or detrimental way that results in personal, professional, or social problems. A patient that is abusing an opioid analgesic may no longer be appropriately interacting with their family, friends, or be able to perform their duties at work. Misuse of a controlled substance refers to the use of a prescribed drug in a way that was not intended. It may be deliberate or accidental. A negative result may or may not occur. Examples of misuse include taking too much of a drug, using an incorrect dose route, or using prescription drugs written for another person. Controlled substances include both prescription drugs and illicit drugs with no recognized medical value. Both have the potential to be abused or misused. While schedule I drug use is illegal, prescription drugs found in schedules II-V are also commonly abused and misused, and their misuse is a challenging problem that has increased over the last several years. The Centers for Disease Control and Prevention has declared prescription drug abuse is a problem of epidemic proportions. The CDC believes that absent checks and balances on the prescription and distribution of controlled substances, including those prescribed for medical use, the potential for abuse and misuse will continue to increase. Pill Shopping Unfortunately, a common practice among those that deliberately misuse controlled substances is to seek out multiple sources of drugs. They do this by seeing different health care providers, and they present with a different list of complaints that are often fictitious and different for each provider. The patient may be able to obtain multiple prescriptions and then fill them at different pharmacies. Many states have enacted systems that allow providers to see all of the prescriptions written for each patient. Use of these systems is gradually curbing "pill shopping." Diversion Some prescription drugs will sell on the street for as much as $50 a tablet. Diversion is when a patient sells their drugs as a method of earning money. Drugs may also be sold to buy food, pay expenses, or purchase more potent street drugs. Worse, in some cases, healthcare providers may divert drugs from patients for the providers own personal use or sell them to someone else. Some individuals use controlled substances in ways for which they were not originally intended. Rather than pain control, they may be used to stay awake, induce sleep, or get "high." Before the popularity of prescription drug diversion, the only method to obtain illicit drugs was to import from other countries or manufacture them in private labs. Today, law enforcement agencies have the tremendous challenge of dealing with prescription drugs sold by diversion as well as illicit drugs imported or manufactured. In both instances, these drug sales and usage result in increased criminal activity as well as dangerous overdoses and death. Methods of Obtaining Prescription Drugs A review of multiple studies demonstrates a variety of means individuals obtain prescription drugs. The following summarizes the studies' findings. 55% free from a friend or relative. 20% from a prescriber. 10% purchased from a friend or relative. 5% stolen from a friend or relative. 5% purchased from a drug dealer. 2% from multiple doctors. 1% from theft from medical practice or pharmacy. Less 1% from internet. Studies also reveal the source of the majority of these drugs was a single legal prescriber.
- Analysis of Drugs in Oral Fluid Using LC-MS/MS. [Journal Article]
- MMMethods Mol Biol 2019; 1872:237-259
- Oral fluid analysis for drugs is increasingly used in a variety of testing areas: pain management and medication monitoring, parole and probation situations, driving under the influence of drugs (DUI…
Oral fluid analysis for drugs is increasingly used in a variety of testing areas: pain management and medication monitoring, parole and probation situations, driving under the influence of drugs (DUID), therapeutic drug monitoring, and testing for drugs in the workplace. The sample collection itself is straightforward, rapid, observable, and noninvasive, requiring no special facilities (compared to urine) or medical personnel (compared to blood). The pH of saliva is slightly acidic relative to blood; therefore, drugs which are more basic tend to be present in higher concentration in oral fluid than in blood: cocaine, amphetamines, oxycodone, tramadol, buprenorphine, methadone, and fentanyl. Conversely, acidic drugs and drugs which are strongly protein bound have lower concentrations in oral fluid than in blood: examples include benzodiazepines, barbiturates, and carisoprodol. Because of the low volume of specimen available for analysis and the drug concentrations present (generally much lower than those in urine), efficient extraction methods and sensitive confirmation procedures are necessary for routine analysis of drugs in oral fluid. In this chapter, solid-phase extraction methods are described for a variety of drugs with liquid chromatography-tandem mass spectrometry detection.
- Drugs and Lactation Database (LactMed): Carisoprodol [BOOK]
- BOOKNational Library of Medicine (US): Bethesda (MD)
- If carisoprodol is required by the mother, it is not necessarily a reason to discontinue breastfeeding. Slight sedation has occurred in a breastfed newborn infant who was exposed during pregnancy and…
If carisoprodol is required by the mother, it is not necessarily a reason to discontinue breastfeeding. Slight sedation has occurred in a breastfed newborn infant who was exposed during pregnancy and lactation; sedation might be more pronounced in newborns who are exposed for the first time during nursing. Other agents may be preferred, especially while nursing a newborn or preterm infant, or when other drugs that can cause sedation are used simultaneously.
- Inhibition of In Vitro Metabolism of Opioids by Skeletal Muscle Relaxants. [Journal Article]
- BCBasic Clin Pharmacol Toxicol 2018; 123(3):327-334
- The purpose of this study was to test the hypothesis that skeletal muscle relaxants could inhibit the in vitro metabolism of common comedications opioids buprenorphine, methadone and oxycodone. The c…
The purpose of this study was to test the hypothesis that skeletal muscle relaxants could inhibit the in vitro metabolism of common comedications opioids buprenorphine, methadone and oxycodone. The compounds [solubility-limited concentration (μM) studied] were as follows: baclofen (1000), carisoprodol (200), its metabolite meprobamate (1000), chlorzoxazone (200), cyclobenzaprine (1000), metaxalone (50), methocarbamol (1000), orphenadrine (1000) and tizanidine (1000). Compounds were first incubated with human liver microsomes ± pre-incubation, screened with pathway-specific cDNA-expressed cytochrome P450s (rCYP), and then IC50 values determined using either 8-concentration tests for those where the rCYP screen suggested an IC50 was achievable, or a 3-concentration test with downward extrapolation if screen suggested 50% inhibition was not achievable. These results were then extrapolated to determine an inhibitory potential. Six pathway inhibitor combinations were identified with a moderate inhibitory potential (≥2.0 < 5.0): five with chlorzoxazone, R-EDDP, S-EDDP and noroxycodone production by CYP3A4, and R- and S-EDDP production by CYP2B6; and one for the meprobamate effect on noroxycodone production by CYP3A4. An additional eleven combinations were found with a weak inhibitory potential (≥1.25 < 2.0): five with carisoprodol, two each with methocarbamol and meprobamate, and one each with metaxalone and orphenadrine. This represents the first comprehensive study of the inhibitory effect of this class of drugs and suggests that some of them may produce significant drug-drug interactions with opioids that are frequent comedications with skeletal muscle relaxants.
- Combination pharmacotherapy for the treatment of fibromyalgia in adults. [Review]
- CDCochrane Database Syst Rev 2018 02 19; 2:CD010585
- CONCLUSIONS: There are few, large, high-quality trials comparing combination pharmacotherapy with monotherapy for fibromyalgia, consequently limiting evidence to support or refute the use of combination pharmacotherapy for fibromyalgia.
- Trends in carisoprodol abuse and misuse after regulatory scheduling: a retrospective review of California poison control calls from 2008 to 2015. [Journal Article]
- CTClin Toxicol (Phila) 2018; 56(7):653-655
- CONCLUSIONS: Scheduling of carisoprodol was temporally related to decreased exposures as reported to California Poison Control Centers. Governmental regulation may impact a drug's potential for abuse.
- High-risk prescribing and opioid overdose: prospects for prescription drug monitoring program-based proactive alerts. [Journal Article]
- PAINPain 2018; 159(1):150-156
- To develop a simple, valid model to identify patients at high risk of opioid overdose-related hospitalization and mortality, Oregon prescription drug monitoring program, Vital Records, and Hospital D…
To develop a simple, valid model to identify patients at high risk of opioid overdose-related hospitalization and mortality, Oregon prescription drug monitoring program, Vital Records, and Hospital Discharge data were linked to estimate 2 logistic models; a first model that included a broad range of risk factors from the literature and a second simplified model. Receiver operating characteristic curves, sensitivity, and specificity of the models were analyzed. Variables retained in the final model were categories such as older than 35 years, number of prescribers, number of pharmacies, and prescriptions for long-acting opioids, benzodiazepines or sedatives, or carisoprodol. The ability of the model to discriminate between patients who did and did not overdose was reasonably good (area under the receiver operating characteristic curve = 0.82, Nagelkerke R = 0.11). The positive predictive value of the model was low. Computationally simple models can identify high-risk patients based on prescription history alone, but improvement of the predictive value of models may require information from outside the prescription drug monitoring program. Patient or prescription features that predict opioid overdose may differ from those that predict diversion.
- Population health management in a small health system: Impact of controlled substance stewardship in a patient-centered medical home. [Journal Article]
- AJAm J Health Syst Pharm 2017 Sep 15; 74(18):1468-1475
- CONCLUSIONS: In 2013, Penobscot Community Health Care (PCHC), in Bangor, Maine, was fully engulfed in the prescription opioid crisis. At PCHC, patients' opioid doses were startlingly high. Within the organization, measures to ensure that prescriptions were being used as prescribed, and not diverted, were underutilized. PCHC responded to these challenges by developing a comprehensive approach to controlled substance stewardship, defined as a coordinated effort to promote the appropriate use of controlled substances, improve patient outcomes, reduce misuse and abuse, and decrease patient morbidity and mortality attributed to these high-risk medications. Since the establishment of the program, over 1,300 patient reviews have been conducted. During this time, the number of PCHC patients receiving chronic opioids has decreased by 67.2% and continues to drop, with a corresponding 65.6% decrease in the number of patients receiving benzodiazepines. Premature deaths were reviewed to identify associations with opioids prescribed at the time of death, which revealed a decline of 50% between 2013 and 2015. Since program inception, the reviews conducted based on internal quality-improvement reports have been expanded to include patients on combinations of opioids and benzodiazepines, high-dose opioids, and carisoprodol.Systematic approaches addressing areas of critical need in high-risk populations are integral to PHM efforts in small health systems. The pharmacy team can serve a unique role in identifying, developing, and implementing key PHM services. Coupled with strategic community partnerships, successful PHM integration can assist in the financial survival of small health systems.
- Exploiting the high oxidation potential of carisoprodol on a boron-doped diamond electrode: an improved method for its simultaneous determination with acetaminophen and caffeine. [Journal Article]
- AAnalyst 2017 Sep 08; 142(18):3514-3521
- A boron-doped diamond electrode (BDDE) was employed for the first time in the development of a voltammetric method for the simultaneous determination of acetaminophen (ACT), caffeine (CAF) and cariso…
A boron-doped diamond electrode (BDDE) was employed for the first time in the development of a voltammetric method for the simultaneous determination of acetaminophen (ACT), caffeine (CAF) and carisoprodol (CAR). CAR presents a high oxidation potential (2.0 V) and this electrode is suitable for this purpose due to its wide electrochemical potential window. The anodic peak potentials of ACT, CAF and CAR oxidation on the BDDE were found to be 0.980 V, 1.50 V and 2.03 V (vs. Ag/AgCl (3.0 mol L-1 KCl)), respectively, by cyclic voltammetry. After optimization of the analytical conditions employing BDDE at pH 6.0 in a Britton-Robinson buffer solution, square-wave voltammetry (SWV) was applied to the simultaneous determination, by which the peak currents for the three molecules were found to vary linearly with their concentrations in the range of 2.99-283 μmol L-1 for ACT, 2.99-84.8 μmol L-1 for CAF and 19.9-207 μmol L-1 for CAR, with detection limits of 0.768 μmol L-1, 0.771 μmol L-1, and 3.11 μmol L-1, respectively. The proposed method was employed for the simultaneous determination of the three molecules in pharmaceutical formulations and the results were successfully validated with a comparative spectrophotometric method. The use of BDDE showed advantages such as low cost, suitable linearity for simultaneous quantification in real samples, no adsorption problems, and possessing rapidity and excellent reproducibility. This electrode represents a suitable electrochemical sensor for the routine analysis of these drugs.
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- Primary fibroblasts from CSPα mutation carriers recapitulate hallmarks of the adult onset neuronal ceroid lipofuscinosis. [Journal Article]
- SRSci Rep 2017 07 24; 7(1):6332
- Mutations in the co- chaperone protein, CSPα, cause an autosomal dominant, adult-neuronal ceroid lipofuscinosis (AD-ANCL). The current understanding of CSPα function exclusively at the synapse fails …
Mutations in the co- chaperone protein, CSPα, cause an autosomal dominant, adult-neuronal ceroid lipofuscinosis (AD-ANCL). The current understanding of CSPα function exclusively at the synapse fails to explain the autophagy-lysosome pathway (ALP) dysfunction in cells from AD-ANCL patients. Here, we demonstrate unexpectedly that primary dermal fibroblasts from pre-symptomatic mutation carriers recapitulate in vitro features found in the brains of AD-ANCL patients including auto-fluorescent storage material (AFSM) accumulation, CSPα aggregates, increased levels of lysosomal proteins and lysosome enzyme activities. AFSM accumulation correlates with CSPα aggregation and both are susceptible to pharmacological modulation of ALP function. In addition, we demonstrate that endogenous CSPα is present in the lysosome-enriched fractions and co-localizes with lysosome markers in soma, neurites and synaptic boutons. Overexpression of CSPα wild-type (WT) decreases lysotracker signal, secreted lysosomal enzymes and SNAP23-mediated lysosome exocytosis. CSPα WT, mutant and aggregated CSPα are degraded mainly by the ALP but this disease-causing mutation exhibits a faster rate of degradation. Co-expression of both WT and mutant CSPα cause a block in the fusion of autophagosomes/lysosomes. Our data suggest that aggregation-dependent perturbation of ALP function is a relevant pathogenic mechanism for AD-ANCL and supports the use of AFSM or CSPα aggregation as biomarkers for drug screening purposes.