Opioid withdrawal syndrome is a life-threatening condition resulting from opioid dependence. Opioids are the group of drugs used for management of severe pain. They are also commonly used as psychoactive substances around the world. Opioids include drugs such as morphine, heroin, oxycontin, codeine, methadone, and hydromorphone hydrochloride. They produce mental relaxation, pain relief, and euphoric feelings. Chronic use of opioids leads to the development of incapacitating form of dependence in users. Opioid dependence not only impacts the drug user, but also imposes a significant economic burden on the society by increasing health care costs, unemployment rates, absenteeism, and premature mortality. Studies in some countries have shown that those consequences can cost on average, 0.2% to 2.0% of a country's gross domestic product.
There are 3 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 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 animals models have indicated that symptoms of opioid withdrawal are closely related to pathways of adenylyl cyclase superactivation-based central excitation.
Abuse of heroin and prescription opioids is a long-time concern in the United States. Opioids are also the most common group of drugs abused in places like Asia, Europe, and Oceania, and worldwide consumption of opioid is rapidly increasing. There are approximately 15.6 million illicit opioid users around the globe and consumption of opioids is rapidly increasing. In 2016, an estimated 11.5 million Americans aged 12 years or older abused 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.
The principal site in the brain that triggers an onset of opioid withdrawal syndrome is the locus coeruleus at the base of the brain. Neurons present in locus coeruleus are noradrenergic and have 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, 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.
According to 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 and photophobia, insomnia, autonomic hyperactivity (tachypnea, hyperreflexia, tachycardia, sweating, hypertension, hyperthermia), and yawning.
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, propoxyphene) for 12 to 36 hours after use. Methadone, buprenorphine, and LAAM (L-alpha-acetylmethadol) will not be detected in positive urine opiate test, and they must be specifically tested. Urine toxicology for other drugs(marijuana, cocaine, alcohol, benzodiazepine, and amphetamines) may also be commonly positive in opiate users. ECG, complete blood count (CBC), and basic metabolic panel (BMP) should also be done to check for electrolyte abnormalities.
COWS (Clinical Opioid Withdrawal Scale) assessment for opioid withdrawal is commonly used to determine the severity of opioid withdrawal. The COWS assessment consists of 11 items of commonly seen signs and symptoms of opioid withdrawal. 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. The use of such assessment scales for opiate withdrawal has 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.
When opioid withdrawal signs are present, pharmacological management of opioid withdrawal is done via one of the following:
Methadone is given in inpatient or outpatient treatment setting. Starting dose is 10-mg oral or intravenous (IV) methadone, which may be given every 4 to 6 hours if withdrawal persists. Total dose in 24 hour equals the dose for the next day. Rarely 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 by decreasing 10% or 5 mg/daily of total dosage.
Buprenorphine (sublingual) 4 to 12 mg initially can also be given instead of methadone and tapered over 5- to 10-day period. Buprenorphine can precipitate withdrawal symptoms in opiate dependence patients who don't have withdrawal signs. Thus, it must be started 12 to 18 hours after 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.
Symptomatic treatment in opioid withdrawal includes such loperamide for diarrhea, promethazine for nausea/vomiting, and ibuprofen for myalgia. Clonidine can be given to reduce blood pressure.
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 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.
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 management of opioid withdrawal syndrome. It will be available starting August 2018. Lofexidine hydrochloride is an alpha-2 adrenergic agonist indicated for acute discontinuation of opioids. It works by binding to receptors on adrenergic neurons which reduces and sympathetic tone and decreases the release of norepinephrine (NE). According to FDA guidelines, it can be used up to 14 days.
Currently, there are many ongoing trials in preclinical and clinical stages to help with better understanding and management of 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.
Prognosis and risks are associated with the 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.
According to DSM-5, a complication associated with drug use is increased risk for infectious diseases. Screening tests for hepatitis A, B, and C virus 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. In some cases, liver function tests may also be elevated due to toxic injury to the liver due to substances that might be mixed with opioids or from resolving hepatitis. 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 nasal mucosa which can sometimes lead to perforation of 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 abuse opioids.
Most chronic opioid users require rehabilitation care after management of acute withdrawal symptoms as well as outpatient follow up with a psychiatrist.
Consult with an addiction healthcare professional in instances of acute opioid withdrawal management and detoxification program admission.
Patients must be educated about risks associated with using opioids. The patient should also be advised not to stop taking opioids abruptly, and if they wish to discontinue using opioids, they should consult a physician for medically supervised detoxification.
One of the major cause of opioid withdrawal in the United States is an abuse of prescription pain drugs. Physicians and other healthcare providers must be careful in prescribing opioids to their patients. Healthcare providers should only provide a limited prescription of opioids when it is of the essential need to their patients.
Treating opioid withdrawal requires interprofessional teamwork by psychiatrists, nurses, social workers, therapists, pharmacists, and other healthcare professionals. The patient is initially stabilized in the emergency room setting before being transferred to an inpatient or outpatient drug detoxification unit. In an inpatient detoxification unit, nurses, therapists, and psychiatrists work together manage symptoms before a patient is discharged to an outpatient program and follow-up with a psychiatrist. Thus, comprehensive care by multiple healthcare professionals is required to treat and manage an opioid withdrawal patient. Keys to working efficiently in a team is having proper communication and respect of opinion of other healthcare providers. Most importantly, the patient should be actively involved in treatment decisions, and their needs must also be addressed.
|||Opioid withdrawal syndrome: emerging concepts and novel therapeutic targets., Rehni AK,Jaggi AS,Singh N,, CNS & neurological disorders drug targets, 2013 Feb 1 [PubMed PMID: 23244430]|
|||Scavone JL,Sterling RC,Van Bockstaele EJ, Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal. Neuroscience. 2013 Sep 17 [PubMed PMID: 23624062]|
|||Buprenorphine Therapy for Opioid Use Disorder., Zoorob R,Kowalchuk A,Mejia de Grubb M,, American family physician, 2018 Mar 1 [PubMed PMID: 29671504]|
|||Tompkins DA,Bigelow GE,Harrison JA,Johnson RE,Fudala PJ,Strain EC, Concurrent validation of the Clinical Opiate Withdrawal Scale (COWS) and single-item indices against the Clinical Institute Narcotic Assessment (CINA) opioid withdrawal instrument. Drug and alcohol dependence. 2009 Nov 1 [PubMed PMID: 19647958]|
|||Wesson DR,Ling W, The Clinical Opiate Withdrawal Scale (COWS). Journal of psychoactive drugs. 2003 Apr-Jun [PubMed PMID: 12924748]|
|||Choy M, Pharmaceutical Approval Update. P [PubMed PMID: 30100686]|
|||Fatseas M,Denis C,Massida Z,Verger M,Franques-Rénéric P,Auriacombe M, Cue-induced reactivity, cortisol response and substance use outcome in treated heroin dependent individuals. Biological psychiatry. 2011 Oct 15 [PubMed PMID: 21741031]|
|||Opioid analgesics: does potency matter?, Passik SD,Webster L,, Journal of opioid management, 2014 Jul-Aug [PubMed PMID: 25162606]|