Opioid withdrawal is a set of symptoms arising from the sudden cessation or reduction of where previous usage has been heavy and prolonged.
Signs and symptoms
Withdrawal from any opioid produces similar signs and symptoms. However, the severity and duration of withdrawal depend on the type and dose of
opioid taken and the duration and frequency of use.
The symptoms of opioid withdrawal may develop within minutes or up to several days following reduction or stopping.
The withdrawal from various opioid medications, including morphine, causes similar effects, most of which is caused by stimulation and over-stimulation of the central nervous system.
Short-term withdrawal symptoms
The onset of withdrawal symptoms varies with the duration of action of the medication. For instant-release morphine (shorter duration of action), withdrawal symptoms begin 8 to 24 hours after the last dose and persist for 4 to 10 days. For extended-release morphine (longer duration of action), withdrawal symptoms begin 12 to 48 hours after the last dose and persist for 10 to 20 days.
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Initial symptoms include: an agitated state, feeling anxious, Myalgia, increased tears, insomnia, runny nose, excessive sweating, and .
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Late symptoms include: Abdominal pain, diarrhea, pupil dilation, Goose bumps, nausea, vomiting.
Long-term withdrawal symptoms
Withdrawal from opioids such as morphine also leads to a extended withdrawal phase.
It persists for up to half a year, and is categorised by a strong craving for opioids and a decline in
well-being.
Pathophysiology
Repeated dosages of opioids can quickly lead to
Drug tolerance and physical dependence. This is due to the marked decrease in
opioid receptor sensitivity caused by long-term receptor stimulation triggering receptor desensitisation (in this case receptor internalisation).
Tolerance causes a decrease in opioid sensitivity, impairing the efficacy of endogenous (our own body's) opioid molecules that function in multiple brain regions. Opioids partially signal through the decrease in cellular cAMP. Cells with decreased cAMP adapt to regulate cAMP and increase production. In the tolerant brain the sudden withdrawal of opioids coupled with the reduced sensitivity to inhibitory signals from the endogenous opioid systems can cause abnormally high levels of cAMP that may be responsible for withdrawal behaviours.
Similar changes may also be responsible for the peripheral gastrointestinal effects such as diarrhea, as there is a reversal of the effect on gastrointestinal motility.
While morphine is primarily indicated as an analgesic (painkiller), morphine and other opioids are also abused due to the Euphoria feeling and mental relaxation experienced when taken.
Due to the difference in lipophilicity and mode of release between different opioids, the severity and duration of withdrawal symptoms may differ.
The followings are the general descriptions of duration of opioid withdrawal symptoms:
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High intake for a long duration (> 6 months) is associated with a more severe level of withdrawal symptoms.
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Short-acting or instant-release opioids result in more rapid onset and shorter duration of withdrawal symptoms.
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Longer-acting opioids result in slower onset but longer duration of withdrawal symptoms.
Diagnosis
The diagnosis of opioid withdrawal requires recent use or exposure to opioids and symptoms consistent with the disorder.
The severity of symptoms can be assessed by validated withdrawal scales, such as the Clinical Opiate Withdrawal Scale (COWS).
There is no test to diagnose for morphine withdrawal.
Treatment
Treatment for opioid withdrawal is based on underlying diagnostic features. A person with an acute opioid withdrawal but no underlying opioid use disorder can be managed by slowly reducing opioids and treatments aimed at the symptoms.
Monitoring and management
Monitoring of patients’ symptoms and complications from morphine withdrawal should be done 3 to 4 times a day.
Monitoring and subsequent management can be determined via the Short Opiate Withdrawal Scale or the Clinical Opioid Withdrawal Scale.
The scores obtained from the scales vary based on the current symptoms a person with morphine withdrawal is suffering from, where different severities of withdrawal are identified based on these scores along with the respective treatment strategies. For the Short Opiate Withdrawal Scale, a score of 0–10 indicates mild withdrawal, while 10–20 indicates moderate withdrawal, and 20–30 indicates severe withdrawal.
Acute withdrawal
Alpha-2 adrenergic receptor agonists
A major feature of opioid withdrawal is exacerbated
norepinephrine (noradrenaline) release in the
locus coeruleus. Alpha-2 adrenergic receptor agonists can be used to manage the symptoms of acute withdrawal.
Lofexidine and
clonidine are used for this purpose; both are considered to be equally effective, though clonidine has more side effects than lofexidine.
Clonidine is an alpha-2 adrenergic agonist primarily used in the treatment of hypertension.
GABA analogues
While some studies indicate that
gabapentin does not significantly reduce the symptoms of opioid withdrawal, there is increasing evidence that
Gabapentinoid are effective in controlling some of the symptoms during opioid detoxification.
Pregabalin, another
GABA analogue, was more effective than clonidine in reducing opioid withdrawal symptoms.
[ Pregabalin for Opiate Withdrawal Syndrome ClinicalTrials.gov ID NCT03017430. 2020-04-07]
Withdrawal in opioid use disorder
The treatment of withdrawal in people with opioid use disorder also relies on symptomatic management and tapering with medications that replace typical opioids, including
buprenorphine and
methadone. The principle of managing the syndrome is to allow the concentration of drugs in blood to fall to near zero and reverse physiological adaptation. This allows the body to adapt to the absence of drugs to reduce the withdrawal symptoms. The most commonly used strategy is to offer opioid drug users long-acting opioid drugs and slowly taper the dose of the drug. Methadone, buprenorphine/naloxone, and
naltrexone are all commonly used medications for opioid use disorder.
A review of UK hospital policies found that local guidelines delayed access to substitute opioids. For instance, requiring lab tests to demonstrate recent use or input from specialist drug teams before prescribing. A lack of access to these substitutes may increase the risk of people discharging themselves early against medical advice.
Buprenorphine and Methadone
Buprenorphine is an FDA-approved medication that can be prescribed in clinics to treat opioid dependence.
It is a
partial agonist to opioid receptors.
It is used as a low-potency substitute (comparatively weak) to treat dependency to more-potent opioids such as morphine and
heroin, and functions by alleviating withdrawal symptoms and cravings to opioids.
, a drug that blocks the opioid receptors, may be added to the medication regimen to avoid misuse of buprenorphine.
Under the Mainstreaming Addiction Treatment (MAT) Act, buprenorphine is prescribed in events of opioid misuse.
Methadone is an opioid agonist also used to treat opioid dependence. Similar to buprenorphine, methadone reduces cravings to opioids and symptoms of withdrawals.
Buprenorphine should be used with caution if the patient has diabetes, respiratory problems, or urethral obstruction, while methadone should be used in caution if the patient has problems such as respiratory problems and Liver disease.
Psychosocial therapy
In addition to drug therapy,
psychosocial intervention is also used to reduce the
relapse of morphine addiction.
Some interventions are given below based on the severity of morphine dependence.
For patients with lower severity of opioid dependency
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Education on Drugs: Allow the patient to understand how the drug affects the brain to learn to manage the craving.
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Refusing Drugs: Educate the patient to refuse drugs, as they may come across the opportunity again.
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Acceptance and relaxation training: Train the patient to understand how to cope with negative feelings to prevent them from resorting to drugs.
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Planning: Teach the patient to have a plan when leaving a closed setting to reduce the risk of relapse.
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Contingency Management: using positive reinforcement to encourage drug-free behaviors.
For patients with greater severity of dependence (in addition to the four interventions above)
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Finding motivations to reduce drug use: Guide the patient to find a reason for them to reduce or stop drug use.
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Cognitive behavioral therapy: Allow the patient to understand negative, unreasonable thoughts and guide them to replace them with realistic thoughts.
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Problem solving skills: Allow the patient to understand that drugs are not a solution to problems that arise.
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Craving management: Teach the patient how to manage cravings when they experience it.
Dangerous or ineffective treatments
The expense of opioid replacement treatments in some countries has led some people to try treatments with limited evidence. At high doses,
loperamide has been reported by some drug users to alleviate opioid withdrawal syndrome.
The doses reported in the literature are associated with a high risk of damage to the heart.
Neonatal opioid withdrawal
Many thousands of newborns each year are affected by being exposed to opioids during their prenatal development.
Maternal use of opioids has become prolific. The use of opioids during pregnancy creates a dependency in the newborn who experiences
drug withdrawal shown in clinical signs of opioid withdrawal. These signs are grouped as the
neonatal opioid withdrawal syndrome, also known more broadly as neonatal abstinence syndrome.
The central nervous system (CNS), and the autonomic nervous system (ANS) are affected.
Common signs associated with the CNS are high-pitched crying, reduced sleep,
,
, gastrointestinal dysfunction, and
vomiting. Common ANS-associated signs include
Perspiration,
hyperthermia,
,
Sneeze,
Hyperventilation, and
nasal congestion.
Pathophysiology
dopaminergic pathway and neuron adaptations are two possible mechanisms that lead to the development of morphine dependence and withdrawal symptoms.
Dopaminergic pathway
Addiction to opioids such as morphine occur due to the changes in the dopaminergic signalling of the
Reward system as a result of chronic opioid use.
Changes to the dopaminergic signalling gives rise to drug craving behavior.
Changes to the dopaminergic signalling leads to signs and symptoms of morphine withdrawal when amount of morphine is reduced or discontinued.
The impairment of the dopaminergic signalling also leads to a decrease in
dopamine (a neurotransmitter used to transmit signals across nerve cells in the central nervous system) in the mesocorticolimbic system, otherwise known as the
reward system, which is suggested to have a critical role in morphine withdrawal.
It can lead to morphine
sensitization, or tolerance, such that more morphine is needed to achieve the same pharmacological effect.
Neuron adaptation
Addiction to morphine may also arise due to various adaptations of the
, including the desensitization of the μ-opioid receptor (MOR), the impairment of the
Cell signaling of MOR, the changes in brain systems that interact with neurons sensitive to μ-opioid receptors, and the activation of supporting cells in the brain known as
Glia.
In the sudden discontinuation or reduced dose of opioids, physiological responses occur in response to the decreased occupancy of the μ-opioid receptor, thus producing signs and symptoms of morphine withdrawal.
See also
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Opioid-induced hyperalgesia
Further reading
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Kosten, T. R., & Baxter, L. E. (2019). Review article: Effective management of opioid withdrawal symptoms: A gateway to opioid dependence treatment. American Journal on Addictions, 28(2), 55–62.
