Opioid Withdrawal

Etiology

There are three types of opioid receptors; mu, delta, and kappa. They are G protein-coupled receptors that inhibit adenyl cyclases in various tissues and cause their pharmacologic actions by decreasing cyclic adenosine monophosphate levels. The mu receptor is crucial for reinforcing the actions of opioids.

Opioid withdrawal occurs when a patient who is dependent on opioids suddenly reduces or stops taking opioids. It can also be caused when a patient has an opioid in his/her system and is given an opioid partial agonist like buprenorphine or antagonists like naloxone or naltrexone. The etiology of opioid withdrawal is complex. Studies from various in vivo and in vitro animal models have indicated that symptoms of opioid withdrawal are closely related to pathways of adenylyl cyclase superactivation-based central excitation.[1]

Epidemiology

Misuse of heroin and prescription opioids is a long-time concern in the United States.[2] Opioids are also the most common group of drugs misused in places like Asia, Europe, and Oceania, and worldwide consumption of opioids is rapidly increasing.[1] There are approximately 15.6 million illicit opioid users worldwide, and the consumption of opioids is rapidly increasing. In 2016, an estimated 11.5 million Americans aged 12 years or older misused opioid pain medications. Of that, 1.8 million had substance use disorder resulting from prescribed pain medications. From 2000 through 2015, approximately 500,000 people died from opioid overdoses. Clinicians wrote 259 million prescriptions in 2012 for opioids, enough for every adult in the United States.[3]

Pathophysiology

The principal site in the brain that triggers the onset of opioid withdrawal syndrome is the locus coeruleus at the base of the brain. Neurons present in locus coeruleus are noradrenergic and have an increased number of opioid receptors. The locus coeruleus region is the main source of NAergic innervation of the limbic system and cerebral and cerebellar cortices. The NAergic activity in locus coeruleus neurons, an opioid receptor linked mechanism, is a prime causative site of opioid withdrawal symptoms. Furthermore, research has also shown that gray matter and nucleus raphe magnus is also involved in the presentation of opioid withdrawal syndrome.[1]

History and Physical

According to the Diagnostic and Statistical Manual of Mental Disorders (DSM–5) criteria, signs and symptoms of opioid withdrawal include lacrimation or rhinorrhea, piloerection "goose flesh," myalgia, diarrhea, nausea/vomiting, pupillary dilation, photophobia, insomnia, autonomic hyperactivity (tachypnea, hyperreflexia, tachycardia, sweating, hypertension, hyperthermia), and yawning.

Evaluation

Although there is no diagnostic test for opioid withdrawal, urine toxicology must be checked to rule out withdrawal from any other drugs or combination of drugs. Urine toxicology is positive for most opioids such as morphine, heroin, codeine, oxycodone, and propoxyphene) for 12 to 36 hours after use. Methadone, buprenorphine, and LAAM (L-alpha-acetylmethadol) will not be detected in positive urine opiate tests, and they must be specifically tested. Urine toxicology for other drugs (marijuana, cocaine, benzodiazepine, and amphetamines) may also be commonly positive in opiate users. ECG, complete blood count (CBC), blood alcohol level, and basic metabolic panel (BMP) should also be done.

COWS (Clinical Opioid Withdrawal Scale) assessment for opioid withdrawal is commonly used to determine the severity of opioid withdrawal.[4] The COWS assessment consists of 11 commonly seen signs and symptoms of opioid withdrawal.[5] The total scores, 0 to 47, range from mild (5 to 12), moderate (13 to 24), moderately severe (25 to 36), and severe (greater than 37) opioid withdrawal. Such assessment scales for opiate withdrawal have gained increased interest as buprenorphine, a partial mu receptor agonist used to treat opioid withdrawal, can precipitate withdrawal in opioid-dependent patients who are not experiencing any withdrawal symptoms.[5]

Treatment / Management

When opioid withdrawal signs are present, pharmacological management of opioid withdrawal is needed. Long-term opioid replacement is accomplished using methadone or buprenorphine. 

Methadone is given in inpatient or outpatient treatment settings. The starting dose is 10 mg oral or intravenous (IV) methadone, which may be given every 4 to 6 hours if withdrawal persists. The total dose in 24 hours equals the dose for the next day. Rarely does a patient needs more than 40 mg in 24 hour period. On the second day, the determined dose can be given once or twice a day. Titration is begun on the third day to determine a maintenance dose.

Buprenorphine (sublingual) 4 to 12 mg initially can also be given instead of methadone. Buprenorphine can precipitate withdrawal symptoms in opiate dependent patients who do not have withdrawal signs. Thus, it must be started 12 to 18 hours after the last use of short-acting agonists like heroin or oxycodone and 24 to 48 hours after the last use of long-acting agonists such as methadone.[6](B2)

Symptomatic treatment in opioid withdrawal includes loperamide for diarrhea, promethazine for nausea/vomiting, and ibuprofen for myalgia. Clonidine can be given to reduce blood pressure.

Mainstreaming Addiction Treatment (MAT) Act

The Mainstreaming Addiction Treatment (MAT) Act provision updates federal guidelines to expand the availability of evidence-based treatment to address the opioid epidemic. The MAT Act empowers all health care providers with a standard controlled substance license to prescribe buprenorphine for opioid use disorder (OUD), just as they prescribe other essential medications. The MAT Act is intended to help destigmatize a standard of care for OUD and will integrate substance use disorder treatment across healthcare settings. 

As of December 2022, the MAT Act has eliminated the DATA-Waiver (X-Waiver) program. All DEA-registered practitioners with Schedule III authority may now prescribe buprenorphine for OUD in their practice if permitted by applicable state law, and SAMHSA encourages them to do so. Prescribers who were registered as DATA-Waiver prescribers will receive a new DEA registration certificate reflecting this change; no action is needed on the part of registrants.

There are no longer any limits on the number of patients with OUD that a practitioner may treat with buprenorphine. Separate tracking of patients treated with buprenorphine or prescriptions written is no longer required. 

Pharmacy staff can now fill buprenorphine prescriptions using the prescribing authority's DEA number and does not need a DATA 2000 waiver from the prescriber. However, depending on the pharmacy, the dispensing software may still require the X-Waiver information in order to proceed. Practitioners are still required to comply with any applicable state limits regarding the treatment of patients with OUD.  Contact information for State Opioid Treatment Authorities can be found here: https://www.samhsa.gov/medicationassisted-treatment/sota.  

Differential Diagnosis

According to DSM-5, the following disorders must be ruled out first when treating a patient with opioid withdrawal.

Opioid-Induced Mental Disorders

Commonly co-occurring in opioid drug users and can be characterized by symptoms that occur in primary mental disorders. Such symptoms include depressed mood, persistent depressive disorder (dysthymia), and opioid-induced depressive disorder. Opioid withdrawal differs from other opioid-induced disorders because symptoms in other disorders predominate clinical presentation and warrant further diagnostic investigation.

Other Substance Intoxication

Alcohol intoxication, hypnotic, or anxiolytic intoxication can cause a similar clinical presentation of opioid intoxication and must also be ruled out.

Other Withdrawal Disorders

Sedative-hypnotic withdrawal symptoms may resemble opioid withdrawal characteristics, but opioid withdrawal is also characterized by lacrimation, rhinorrhea, and pupillary dilation. Hallucinogen and stimulant intoxication can also cause pupillary dilation, but other symptoms of opioid withdrawal-like nausea, diarrhea, vomiting, lacrimation, and rhinorrhea, are usually not present.

Pertinent Studies and Ongoing Trials

There are recent updates to the current management of opioid withdrawal syndrome. In May 2018, the FDA approved lofexidine hydrochloride, the first non-opioid for managing opioid withdrawal syndrome. It received FDA approval in 2018. Lofexidine hydrochloride is an alpha-2 adrenergic agonist indicated for the acute discontinuation of opioids. It works by binding to receptors on adrenergic neurons, which reduces and sympathetic tone and decreases norepinephrine release (NE).[7] According to FDA guidelines, it can be used for up to 14 days.

Currently, there are many ongoing trials in preclinical and clinical stages to understand better and manage opioid addiction and withdrawal syndromes. In the preclinical stages, there is a possibility of developing a vaccine against opioid addiction, which can block opioid effects and could provide a better alternative to currently available treatment options. There are also many other active studies evaluating various other pharmacological targets to manage opioid withdrawal syndrome better.[1]

Prognosis

Prognosis and risks are associated with various individual, family, social, environmental, and peer factors. According to DSM-5, genetic factors also play a crucial role directly and indirectly. Opioid users who have a strong support system, good impulse control, and are genetically favored are likely to have a better prognosis. Furthermore, patients who are likely to follow up with their outpatient care with a psychiatrist and/or detoxification program are also likely to have a favorable prognosis.

Complications

According to DSM-5, a complication associated with drug use is an increased risk for infectious diseases. Screening tests for hepatitis A, B, and C viruses are positive in approximately 80% to 90% of injection opioid users. HIV is also positive for many injection drug users. HIV rates have been reported as high as 60%, specifically for opioid users in some parts of the United States and the Russian Federation, but it might be low at 10% in other areas.[8] In some cases, liver function tests may also be elevated due to toxic injury to the liver due to substances mixed with opioids or resolving hepatitis.[9] Furthermore, tetanus and Clostridium botulinum, although rare, are serious complications of injection opioid users. Tuberculosis is also a serious problem with injection drug users, especially heroin drug users. Infection is usually asymptomatic and usually indicated by a positive tuberculin skin test. Users who snort heroin or other opioids develop irritation of the nasal mucosa, which can sometimes lead to perforation of the nasal septum. Sexual side effects are also common. Male opioid drug users often experience erectile dysfunction, and females have disturbances in menses and irregular reproduction. Physiological disturbances and low birth weight can also be seen in infants born to women who use opioids.