Opioid Withdrawal (OW)
Opioid Withdrawal (OW) is a collection of symptoms that occur when blood opioid levels abruptly decrease in patients who have developed physical dependence from repeated or chronic opioid use. Symptoms occur when use of opioids is suddenly stopped or doses are markedly reduced and can be associated with use of prescription opioids for chronic pain or with illicit use of opioids related to substance abuse or addiction.
Treating Opioid Withdrawal:
Alpha-2 Adrenergic Agonists – Catapres (clonidine), Lucemyra (lofexidine)
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Opioid Withdrawal (OW)
The collection of symptoms associated with abruptly stopping or markedly reducing one’s chronic dose of opioids is referred to as Opioid Withdrawal (OW) syndrome. Symptoms include muscle aches (myalgias), joint pains (arthralgias), headaches, nausea, vomiting, abdominal cramps, diarrhea, sweating, malaise, fatigue, agitation, insomnia, dysphoria (a profound, undesirable mood of unease and dissatisfaction), and other symptoms. OW symtoms typically peak in 2-4 days and persist for 7-10 days, but some patients report persisting OW that last for weeks to months.
Withdrawal-induced hyperalgesia (WIH) is a distinct entity that may accompany the OW syndrome which is an increased sensitivity to pain, characterized by a magnified perception of pain as well as a lower threshold for a stimulus to be perceived as painful.
Factors Influencing Severity of Opioid Withdrawal
Factors influencing the severity of opioid withdrawal symptoms have only been examined in a few studies. Most of the predictors can be divided into drug-related or person-related factors. Examples of drug-related factors are the type of opioid, opioid dose and method and duration of opioid use. While anecdotal reports suggest some opioids to be associated with worse OW symptoms, this has not been well studied. Use of opioids with long duration of action, or long half-lives, such as time-release preparations will have a more gradual and, at least initially, a less severe onset of OW. The higher the dose and the longer duration of use appear to be associated with more severe OW. While studies are mixed, it is reported that use of intravenous injected opioids is associated with greater severity than oral-use opioids.
Regarding person-related variables, no sociodemographic characteristics have been found to relate to withdrawal symptoms. Factors such as anticipation of withdrawal severity and neuroticism have been found to be associated with withdrawal symptoms. Both these factors are anxiety related and are therefore likely to amplify withdrawal symptoms. People with antisocial personality disorders tend to have worse withdrawal symptoms.
Prevention of OW
Rather than abruptly stopping opioids, tapering down slowly will reduce the risk and/or severity of OW. Additionally, rotating to an alternative opioid prior to tapering may also be effective. Rotating to buprenorphine may be especially helpful.
See: Tapering off Opioids
Treatment of OW
Current methods of treating withdrawal are inadequate. Medications most commonly used for opioid detox- ification and treatment of OW include opioids and nonopioid drugs such as the a2-agonist clonidine and ondansetron. However, these medications do not completely eliminate withdrawal symptoms.
Opioids for Opioid Withdrawal
When the long-term goal of treating OW includes discontinuing use of opioids for pain, the best, most commonly prescribed opioid for OW is buprenorphine (Suboxone, Zubsolv and Bunavail). It is very effective but the transition to buprenorphine may initially require the patient to experience mild to moderate OW symptoms that cannot always be accurately predicted.
When the long-term goal of treating OW is discontinuing use of illicit opioids for addiction, buprenorphine is also the best, most commonly prescribed opioid. Methadone is also used for detoxification in opioid addiction. Historically effective, it nevertheless is more complicated to prescribe, requires a special license to prescribe for addiction, and is fraught with safety concerns.
Non-Opioids for Opioid Withdrawal
Selective alpha 2-adrenergic receptor agonists (Alpha 2-Agonists)
Selective alpha 2-adrenergic receptor agonists reduces the release of norepinephrine, a neurotransmitter in the autonomic nervous system similar to adrenaline (epinephrie) which plays a role in many of the symptoms of opioid withdrawal. These symptoms include feeling sick, stomach cramps, muscle spasms/twitching, feeling of coldness, heart pounding, muscular tension, aches and pains, yawning, runny eyes and insomnia/problems sleeping.
The two alpha 2 agonists currently available for treating opioid withdrawal include Lucemyra (lofexidine) and clonidine, both medications historically used to treat high blood pressure. As such, one of their potential side effects is a drop in blood pressure, which may manifest as weakness or light-headedness. Other side effects may include bradycardia (slow heart rate), drowsiness, dizziness and possible fainting. They may also effect the heart’s electrical activity, which can result in abnormal heart rhythms and palpitations.
It is advised to be careful to stay well-hydrated by drinking plenty of fluids, since dehydration will predispose to dropping blood pressure. If the blood pressure drops below 90-100/60, alpha 2 agonists should be withheld and fluids provided. When alpha 2 agonists are suddenly stopped, patients can experience a sudden increase in blood pressure so it may be best to slowly taper them off and monitor blood pressure in the process. A Cochrane review concluded that lofexidine had less effect on blood pressure than clonidine.
Lucemyra (lofexidine hydrochloride)
The U.S. Food and Drug Administration (FDA) recently (May, 2018) approved Lucemyra (lofexidine) for the treatment of withdrawal symptoms related to suddent discontinuation of opioids in adults. Lofexidine has been used in Great Britain and has been shown to be effective. Although Lucemyra may lessen the severity of withdrawal symptoms, it may not completely prevent them. Lucemyra is only approved for treatment for up to 14 days, not for long-term treatment.
The oral dose of lofexidine is 0.8 mg (4 × 0.2 mg lofexidine HCl tablets) three to four times daily for a total daily dose of 2.4 to 3.2 mg/day, although it is recommended to initiate treatment with the lower dose to avoid side effects.
The safety and effectiveness of Lucemyra has not been established in children or adolescents less than 17 years of age.
Clonidine has been used since the 1980s to treat the nervous system symptoms caused by noradrenergic hyperactivity associated with withdrawal. While not FDA approved for use in OW, clonidine has been commonly used off label for years for managing OW. However, the overall effectiveness of clonidine is only moderate in reducing withdrawal symptoms, and is less effective than opioids at relieving anxiety, sleeplessness, muscle aches and craving associated with OW.
Clonidine is also associated with potentially severe side-effects such as low blood pressure and sedation that limit its use. Because of this, dosing must be cautious, starting with low doses of 0.025 – 0.05 mg up to 4x/day and monitoring blood pressure.
Ondanstron (Zofran – 5HT3-antagonist)
Ondansetron (Zofran), commonly prescribed for nausea of multiple causes, may also be particularly helpful in both the nausea and other symptoms of opioid withdrawal including the hyperalgesia (increased pain sensitivity) associated with withdrawal. Ondansetron blocks the 5-HT3 receptors that modulate serotonin activity of the mesolimbic system, an area of the brain heavily implicated in withdrawal to multiple substances, including nicotine, alcohol, benzodiazepines (Valium, Xanax, etc.) and cocaine.
Ondansetron is the drug of choice to prevent nausea in women undergoing cesarean surgery and can be used to prevent neonatal abstinence syndrome (NAS), the condition of opioid withdrawal symptoms experienced by newborns when delivered by an opioid-dependent woman. Ondansetron can be given intravenously to the mother at time of delivery where the medication then crosses over to the neonate via placental blood flow and subsequently protects the newborn from OW.
Ondansetron is tolerated well and has an excellent safety record. It is typically dosed at 4-8mg 2-3x/day.
Gabapentinoids (Gabapentin (Neurontin) and Pregabalin (Lyrica)
There is growing evidence that gabapentin (Neurontin) and pregabalin (Lyrica) may be effective OW. Current research indicates that the gabapentinoids, gabapentin and pregabalin, have multiple mechanisms by which they reduce withdrawal symptoms, including hyperalgesia, and some of these mechanisms suggest potential benefit in reducing OW and WIH.
NMDA antagonists (e.g., memantine, dextromethorphan, ketamine, amantadine and others) may minimize opioid tolerance and may reduce opioid withdrawal symptoms. Studies remain limited at this time but offer optimistic evidence for benefit.
A recent 2015 study evaluated the use of memantine in conjunction with buprenorphine in young adults (average age 22 y/o) with opioid addiction. Patients were placed on a short 9-week course of buprenorphine as a detox regimen along with memantine 15mg/day or 30mg/day vs. placebo. In comparism with the 15mg/day or placebo treatment groups, memantine 30mg/day offered the following benefits:
(1) Craving for opioids was significant reduced.
(2) Opioid withdrawal symptoms were significantly reduced.
(3) Reduced early opioid use relapse after rapid buprenorphine discontinuation at week 9.
(4) No serious adverse events
Additional information regarding memantine will be uploaded in the near future.
Dextromethorphan, an over-the-counter cough suppressant (Delsym, Robitussin DM etc.), has weak NMDA antagonist activity and may suppress opioid withdrawal symptoms. Early studies suggested that doses of 360 mg/day dextromethorphan was effective in managing opioid withdrawal, whereas lower doses of between 60-240mg day were less effective. In one study, dextromethorphan 60 mg 4 times a day provided a beneficial effect in reducing the severity of opioid withdrawal symptoms, notably over days 3-6 of treatment.
DXM benefits in opioid withdrawal have been similar to results with a 60mg dose of memantine, another NMDA antagonist. However, in a recent study using dextromethorphan in combination with quinidine (DXM-Q) it was concluded that while DXM-Q does not promise great benefit when used alone for treatment, it may have a role as an additive medication in the treatment of opioid withdrawal.
Studies have shown also that dextromethorphan may have an additive benefit when used with clonidine. In one study, a combination of dextromethorphan and clonidine resulted in milder opioid withdrawal symptoms compared to clonidine alone. In this study, a 300mg daily dose of dextromethorphan (75mg every 6 hours) resulted in a reduction of symptoms beginning on the second day.
A recently published case study (2016) on use of oral ketamine to prevent opioid withdrawal symptoms in a patient on high-dose oxycodone proved very successful, arguing for further research.
There is a growing body of research suggesting that cannabinoids, particularly cannabidiol (CBD), may be effective for managing opioid withdrawal symptoms as well as reducing opioid cravings associated with opioid addiction. ( See Cannabidiol (CBD): Clinical Use and Dosing).
New Thinking About Opioid Tolerance and Implications for Treatment
Recent research has provided interesting new insights into the mechanisms of how opioid tolerance develops as well as mechanisms of opioid withdrawal symptoms including withdrawal-induced hyperalgesia (See below). As a consequence of these new insights including the role of glial cells, there is a growing appreciation for the potential role of medications directed at glial cell activation in the management of all of the opioid-related conditions including withdrawal, tolerance and hyperalgesia.
Complementary and Alternative (CAM) Treatments
Passion Flower (Passiflora incarnata)
While there is minimal research regarding the effectiveness of Passion Flower extract for OW, it has a well-established safety record and is commonly believed to be affective for anxiety. A study in 2001 concluded that Passion Flower extract may be effective for OW, especially when given with clonidine.
See Passion Flower
Neurobiology of OW
Opioid withdrawal is believed to result from adaptations on multiple levels within the nervous system. The brain regions contributing to the physical signs of opiate withdrawal include the periaqueductal gray (PAG) area, the locus coeruleus, amygdala, ventral tegmental area, nucleus accumbens, hypothalamus, and spinal cord.
Among the most important brain regions involved in opiate withdrawal is the periaqueductal gray area (PAG). Numerous neurochemical mechanisms in the PAG have been identified that may contribute to the opioid withdrawal syndrome. Chronic opioid treatment causes glial activation in the spinal cord, posterior cingulate cortex, hippocampus, and PAG leading to an upregulation of proinflammatory cytokine release.
Accumulating evidence suggests that glial activation leading to the release of proinflammatory molecules acting on neurons is important in the complex syndrome of opioid dependence and withdrawal. Glia-neuron interactions play an important role in opioid dependence and withdrawal within the PAG. Multiple neurochemical mechanisms are associated with opioid withdrawal including tumour necrosis facor (TNFα), a pro-inflammatory chemical released from activated glial cells that communicate with TNF receptors on PAG neurons.
See: Neurobiology of Pain
Opioid Withdrawal (OW)
OW – Overviews
- Opiate and opioid withdrawal: MedlinePlus Medical Encyclopedia
- Alleviating Symptoms of Withdrawal from an Opioid – 2012
- Opioid withdrawal protocol-final draft 2010
- An Emerging New Paradigm in Opioid Withdrawal – A Critical Role for Glia-Neuron Signaling in the Periaqueductal Gray – 2012
- Pharmacological strategies for detoxification – 2014
- Newer approaches to opioid detoxification – 2012
OW – Treatment, Buprenorphine
OW – Treatment, Complementary and Alternative (CAM)
- Acetyl-L-carnitine in the management of pain during methadone withdrawal syndrome. – 2009
- Passionflower in the treatment of opiates withdrawal: a double-blind randomized controlled trial – 2001 – PubMed – NCBI
OW – Treatment, Alpha 2-Agonists: Lucemyra (lofexidine) & Clonidine
- Clonidine in opiate withdrawal: revi… [Pharmacotherapy. 1981 Sep-Oct] – PubMed – NCBI
- Clonidine, lofexidine and similar medications for the management of opioid withdrawal – 2016
- Is It Prime Time for Alpha2-Adrenocepter Agonists in the Treatment of Withdrawal Syndromes? – 2014
- The Combination Very Low-Dose Naltrexone–Clonidine in the Management of Opioid Withdrawal – 2012
- Alpha₂-adrenergic agonists for the management of opioid withdrawal. – PubMed – NCBI
- FDA approves Lucemyra (lofexidine)for management of opioid withdrawal symptoms in adults – 2018
- Alpha 2-adrenergic agonists for the management of opioid withdrawal – Cochrane summary – 2016
- A phase III, randomized, multi-center, double blind, placebo controlled study of safety and efficacy of lofexidine for relief of symptoms in individuals undergoing inpatient opioid withdrawal – 2017
OW – Treatment, Gabapentin (Neurontin), Pregabalin (Lyrica) & Topiramate (Topamax)
- Gabapentin Effect on Pain Associated with Heroin Withdrawal in Iranian Crack – 2012
- Topiramate in opiate withdrawal- comparison with … [Subst Abus. 2004] – PubMed – NCBI
OW – Treatment, NMDA Antagonists
OW – Treatment, Dextromethorphan
- A double-blind, placebo-controlled trial of dextromethorphan combined with clonidine in the treatment of heroin withdrawal. – PubMed – NCBI
- The Therapeutic Effect of Adding Dextromethorphan to Clonidine for Reducing Symptoms of Opioid Withdrawal – A Randomized Clinical Trial – 2013
- Evaluation of the reinforcing and subjective effects of heroin in combination with dextromethorphan and quinidine – 2011
OW – Memantine (Namenda)
OW – Treatment, Ketamine & Amantadine
- Experience of the use of Ketamine to manage opioid withdrawal in an addicted woman – a case report – 2016
- Amantadine as Augmentation in Managing Opioid Withdrawal with Clonidine – a randomized controlled trial – 2014
OW – Treatment, Ondansetron
- From mouse to man – the 5-HT3 receptor modulates physical dependence on opioid narcotics – 2009
- Ondansetron Pharmacokinetics in Pregnant Women and Neonates – Towards a New Treatment for Neonatal Abstinence Syndrome – 2015
- 5-Hydroxytryptamine Type 3 Receptor Modulates Opioid-induced Hyperalgesia and Tolerance in Mice – 2011
OW – Treatment, Misc.
- Double-blind randomized controlled trial of baclofen vs. clonidine in the treatment of opiates withdrawal. – PubMed – NCBI
- Scopolamine detoxification technique for heroin dependence – a randomized trial – 2013- PubMed – NCBI
- Efficacy of buspirone in the treatment of opioid withdrawal – 2005 PubMed – NCBI
- Early Outcomes Following Low Dose Naltrexone Enhancement of Opioid Detoxification – 2011
- Problem Drinking and Low-Dose Naltrexone-Assisted Opioid Detoxification – 2011
- Very low dose naltrexone addition in opioid detoxification – a randomized, controlled trial – 2009
- Reduction of opioid-withdrawal symptoms with quetiapine. – PubMed – NCBI
- Venlafaxine for acute heroin detoxification: a double-blind, randomized, control trial. – PubMed – NCBI
- Passionflower in the treatment of opiates withdrawal: a double-blind randomized controlled trial – 2001 – PubMed – NCBI
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