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ISMP
QuarterWatch™ (2016 Annual Report)
Part I: Consumers at risk from drug withdrawal symptoms
July 13, 2017

The latest issue of ISMP’s QuarterWatch™ (see box below references) is an annual report that focuses on drugs and specific adverse events that affect large populations and involve substantial numbers of serious injuries reflected in 1.2 million reports submitted to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) during 2016. In Part I of this newsletter feature, we examine the 2016 reporting totals and one critical topic in the 2016 annual report:

  • Previously underestimated drug withdrawal symptoms reported by large populations of patients who have stopped taking opioids, antidepressants, and certain anticonvulsants/neuropathic pain medications, antianxiety drugs, sedative/hypnotic drugs, and various other medications

In Part II, which will appear in the July 27, 2017 newsletter, we will examine the other important clinical issue described in the 2016 annual report—unacceptably high risk of acute injuries linked to oral anticoagulants. The full annual report, which is now available at: www.ismp.org/sc?id=1702, also evaluates the quality and usefulness of the key drug monitoring system in the US, FAERS, and suggests a full-scale modernization of its reporting requirements to achieve better postmarketing drug surveillance in the modern age of digital information.

Adverse Drug Event Report Totals for 2016

In 2016, FDA received 1,165,073 reports of adverse events from the therapeutic use of prescription and over-the-counter (OTC) drugs, a 1.9% decline from the previous year. This marks the first annual decline in new reports since 2000, although when viewed from the perspective of a decade, there has been a large overall increase in the total number of reports submitted to FAERS (e.g., 273,100 in 2007 vs. 1.2 million in 2016). The 2016 total includes 311,790 domestic reports of injuries classified as serious, including 45,255 (14.5%) that were fatal and 110,179 (35.3%) requiring hospitalization. These injuries affected every body system and included severe damage to the kidneys and liver, fatal cardiac events, cancer, potentially life-threatening allergic reactions, as well as neuropsychiatric effects such as depression, suicidal thoughts, and aggressive and violent acts. For 8.1% of the 2016 cases, a medication error contributed to the reported injury. 

Although the largely voluntary FAERS reports capture only a fraction of the severe events and injuries that might be occurring, the therapeutic use of drugs is extensive (4.5 billion outpatient prescriptions dispensed in the US in 2016), and injuries related to medication use are a major public health risk in the same order of magnitude as illicit drug use.

Drugs with Withdrawal Effects

Summary of analysis. Nausea, dizziness, electric shock-like sensations, insomnia, and anxiety—based on the 2016 QuarterWatch™ data, these are the leading symptoms reported by patients who stopped taking a wide variety of psychoactive drugs. While issues involving opioid withdrawal have been well studied, this safety issue extends to drugs used in even larger patient populations, most notably antidepressants, and certain anticonvulsants/neuropathic pain medications, antianxiety drugs, and sedative/hypnotics. For many of these drugs, the severity, duration, and likelihood of withdrawal effects appear to be underestimated in prescribing information and Medication Guides. In some cases, withdrawal effects have been too poorly studied to support adequate estimates of injury rates.

Methods

To identify drugs with withdrawal effects, we selected all of the 2016 reports with a Standardized MedDRA Query preferred term indicating some form of withdrawal syndrome. Then, to be included as a suspect drug, there had to be at least 10 reported cases of withdrawal effects, at least twice as many cases as expected given the total number of adverse event reports for the drug, and at least a 95% probability that the number of withdrawal effects could not have occurred by chance.

Results

Signal drugs. We identified 4,016 cases of drug withdrawal effects, with 42 drugs that met our requirements as a clear and credible signal of drug risk. The overall results are shown in Table 1. The proportional reporting ratio (PRR) reflects how unexpected the finding was. For example, a PRR of 4 means that the number of withdrawal syndrome reports was 4 times more than expected, given the total number of reports for that drug.

The drugs with a credible signal related to withdrawal effects include:

  • 10 antidepressants that inhibit the reuptake of serotonin, including DULoxetine, which had the largest number of withdrawal reports in 2016 (n = 888), PARoxetine, venlafaxine, desvenlafaxine, and sertraline
  •  10 drugs with effects on gamma-aminobutyric acid (GABA) neurotransmission that produce sedative, hypnotic, and antianxiety effects, including widely used benzodiazepines such as clonazePAM, ALPRAZolam, and LORazepam; a common sleep medication, zolpidem; and two synthetic forms of GABA often used to reduce neuropathic pain, pregabalin and gabapentin
  • 13 opioids, including one of the most potent opioids, fentaNYL; the most widely used opioid, HYDROcodone and acetaminophen; as well as drugs used to treat opioid addiction and overdose, buprenorphine, methadone, and naltrexone
  • 2 drugs that block normal signaling from dopamine D2 receptors, including widely used antipsychotics, QUEtiapine and OLANZapine; as well as methylphenidate, which has an indirect effect on dopamine neurotransmission
  • 6 other medications with various mechanisms of action, including a muscle relaxant (baclofen) and an antihistamine (cetirizine)

Withdrawal symptoms. The most frequently reported withdrawal symptoms in 2016 are shown in Table 2. Most individuals had more than one symptom and often several. The occurrence of discontinuation symptoms depended in part on how quickly the discontinued drug was eliminated from the body. For example, for antidepressants, symptoms usually appeared within a few days of stopping the medication. But withdrawal symptoms can begin within hours for short-acting opioids and may not manifest until 30 hours after discontinuation for long-acting opioids.

Discussion

Why withdrawal symptoms occur. The data in Table 1 show that withdrawal effects are (with a few exceptions) linked to the major neurotransmitters or receptors that are the primary targets of psychoactive drugs. When drugs alter the functioning of these neurotransmitter or receptor circuits, the central nervous system usually makes counter adjustments in signal transmission, reuptake, or receptor expression. Cellular receptor changes made in response to the intrusion of psychoactive drugs include receptor upregulation (neurons express more receptors) or downregulation (receptors disappear), and sensitization (more easily triggered) or desensitization (become less responsive). The extent of this neural remodeling varies greatly with the individual patient, drug half-life, dose, and duration of treatment. When the drugs are withdrawn, especially abruptly, a wide array of symptoms may occur as these circuits seek to readjust. For some individuals, discontinuation is easy or accompanied by minor symptoms, and only a short taper period is needed. For others, the effects are more severe, more prolonged, and in a few cases, do not resolve.

What we know about antidepressant withdrawal. While the withdrawal effects of opioids are well studied,1 only a few controlled studies have examined the likelihood of withdrawal symptoms after abrupt discontinuation of antidepressants. An analysis of 6 trials of DULoxetine (ranked #1 in our analysis) showed that 44.4% of patients experienced at least one withdrawal symptom.2 Another comparison showed that 66% of PARoxetine patients and 60% of sertraline patients experienced withdrawal symptoms.3 In a study of venlafaxine, 78% of patients reported withdrawal symptoms.4 Glenmullen, and Breggin et al., describe antidepressant withdrawal symptoms and provide practical advice on discontinuation in their two books,5,6 concluding that the symptoms are most frequent and severe for drugs with a half-life of 12 hours or less, and the least frequent for drugs that remain in circulation for days, notably FLUoxetine. Table 1 confirms the weaker signal for some antidepressants with longer half-lives. The authors also note that initial withdrawal symptoms often mimic the original problem (e.g., depression, insomnia), misleading patients into believing their problems are recurring after discontinuation of an antidepressant.

Where data are lacking. Little clinical study information about withdrawal effects could be found for two groups of drugs, the synthetic GABA agents and antipsychotic drugs. The only discussion in the prescribing information for pregabalin and gabapentin was a brief mention that anti-epileptic drugs should not be discontinued abruptly due to an increased risk of seizures. No discussion of discontinuation could be identified in the package inserts for OLANZapine and QUEtiapine. Further complicating the analysis is the fact that the synthetic GABA agents and antipsychotics are frequently combined with other psychoactive agents, notably antidepressants and benzodiazepines. 

Warnings and controls. Widespread adult exposure to drugs with withdrawal symptoms is compounded by another problem: standard information for physicians and patients is inadequate or misleading for some drugs. For some drug classes, elaborate controls, stark warnings, and other measures are in effect to manage the risks of long-term use and problems that may occur when stopping the drug. In modestly varying degrees, these measures apply to opioids, benzodiazepines, and many other sedatives. On the other hand, warnings and consumer information for some drugs are inadequate.

For example, we surveyed the FDA-approved prescribing information for the three antidepressants with the strongest signals in 2016 and found that none came close to revealing the 44.4% to 78% incidence rate of withdrawal symptoms seen in discontinuation studies.2-4 DULoxetine prescribing information lists 11 withdrawal symptoms (included in Table 2) but notes that each occurred at a “1% or greater” rate. But the first listed symptom, dizziness, was reported to occur in 19% of patients after long-term use.2 While it is true that dizziness occurs in more than 1% of patients, this statement is misleading. The same is true for nausea (9.9%) and anxiety (9.8%).2 While prescribing information recommends monitoring patients for symptoms when discontinuing treatment, no specific details are provided about how long or how slowly antidepressants may need to be tapered. While the Medication Guide warns consumers to never stop an antidepressant without first talking to a healthcare provider, it vaguely suggests that sudden discontinuation “can cause other symptoms.” The prescribing information and Medication Guides for PARoxetine and venlafaxine provide some additional details about withdrawal effects and taper regimens, and the Medication Guides list a few withdrawal symptoms.

Limitations

Neither our list of common withdrawal symptoms nor table of suspect drugs is comprehensive. For example, other information sources or warnings associate abrupt withdrawal of benzodiazepines with seizures and beta-blockers with rebound exacerbation of coronary artery disease. Also, other drugs with actions similar to those identified may share withdrawal effects but didn't have enough reports in 2016 to meet our study criteria.

Conclusions

Both FDA-approved warnings for physicians and information for consumers give little hint of the extent of withdrawal symptoms that many will experience when discontinuing antidepressants and some other drugs. Withdrawal effects for psychoactive drugs are not systematically studied at the time of approval, and disclosure of withdrawal studies that are conducted has been limited. And a Medication Guide just instructing consumers not to stop a medication without consulting a healthcare provider is not an adequate warning, even if some withdrawal symptoms are succinctly mentioned. Furthermore, given that 84.3% of adults who take psychiatric drugs are long-time users,7 we have to wonder how many have tried to discontinue the drugs and may have misinterpreted withdrawal symptoms as a sign that their symptoms were recurring, thus perpetuating long-term use.

The full QuarterWatch™ report can be found at: www.ismp.org/sc?id=1702.

References

  1. Ouyang H, Liu S, Zeng W, Levitt RC, Candiotti KA, Hao S. An emerging new paradigm in opioid withdrawal: a critical role for glia-neuron signaling in the periaqueductal gray. ScientificWorldJournal. 2012;2012:940613.
  2. Perahia DG, Kajdasz DK, Desaiah D, Haddad PM. Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder. J Affect Disord. 2005;89(1-3):207–12.
  3. Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 1998;44(2):77–87.
  4. Fava M, Mulroy R, Alpert J, Nierenberg AA, Rosenbaum JF. Emergence of adverse events following discontinuation of treatment with extended-release venlafaxine. Am J Psychiatry. 1997;154(12):1760–2.
  5. Glenmullen J. The Antidepressant Solution: A Step-by-Step Guide to Safely Overcoming Antidepressant Withdrawal, Dependence, and “Addiction.” New York: Free Press; 2006.
  6. Breggin P, Cohen D. Your Drug May be Your Problem, Revised Edition: How and Why to Stop Taking Psychiatric Medications. Philadelphia, PA: Da Capo Press; 2007.
  7. Moore TJ, Mattison DR. Adult utilization of psychiatric drugs and differences by sex, age, and race. JAMA Intern Med. 2017;177(2):274–5.

 

What is QuarterWatch™?

QuarterWatch™ is the publication of an independent ISMP surveillance program that monitors adverse drug events reported to FDA by manufacturers, health professionals, and the public. The agency releases, for research and data analysis, excerpts of all domestic and foreign reports it receives into the FDA Adverse Event Reporting System (FAERS). The goal is to identify signals that may represent important drug safety issues which often require further investigation to determine their frequency and establish a causal relationship to the suspect drug. 

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