Opioid Use Disorder __________________________________________________________________________
and the Clinical Opioid Withdrawal Scale (COWS). The OOWS is useful for measuring and documenting measur- able symptoms of opioid withdrawal. The SOWS records the patient’s rating of withdrawal on a 16-item scale. The COWS includes 11 items and contains signs and symptoms (both objective and subjective) of withdrawal [107]. In 2014, the FDA cleared the Bridge Neurostimulation System (an electroauricular device) for use in acupuncture. In 2017, the FDA approved a new indication for the device for use in helping to reduce the symptoms of opioid withdrawal [108]. The NSS-2 Bridge is placed behind the patient’s ear and emits electrical pulses to stimulate branches of certain cranial nerves. It can be used for up to five days during the acute phase of withdrawal. In one study, within 30 minutes of using the device, all patients showed a reduction in COWS score of nearly 31% [108]. In 2018, the FDA approved lofexidine for the management of opioid withdrawal symptoms [109]. This agent may be incor- porated into the treatment of adults with opioid withdrawal symptoms for up to 14 days. ACUTE OPIOID WITHDRAWAL Most research regarding acute withdrawal from an opioid has been conducted with heroin users. Withdrawal symptoms are the result of mu-agonist withdrawal in the case of heroin and begin approximately eight hours after the last dose. The symp- toms begin slowly, peak at 48 to 72 hours, and then gradually taper during the next four to seven days [104]. As noted, typical symptoms of withdrawal include agitation, anxiety, piloerec- tion, tachycardia, mild hypertension, and pupillary mydriasis. Approximately 8 to 12 hours after the last dose, increases in vital signs, pulse, blood pressure, and respiratory vital rate are observed. At the peak, pronounced anxiety, tremors, shakes, smooth and skeletal muscle cramps, and joint and deep bone pain begin to manifest [8]. PROTRACTED WITHDRAWAL Withdrawal symptoms may persist long after elimination of the opioid agent. Such persistent behavioral change suggests plastic alternation within the nervous system, some of which may be mediated by the regulation of gene expression [103]. Chronic exposure to opioids may be associated with changes to the mu receptor, resulting in the propagation of signal transduction in the absence of an agonist. The withdrawal phase can be extended due to the cellular changes that occur after long-term opioid exposure [80]. PERSISTENT NEUROADAPTATION AND RELAPSE VULNERABILITY Opioid dependence is a chronic relapsing disorder character- ized by compulsive drug seeking and use. More than 80% of addicts relapse to drug seeking and use after a period of absti- nence during the protracted withdrawal phase, underscoring the long-standing nature of the compulsion and high rates of recidivism [110]. Two important brain alterations occur follow-
ing dependence and withdrawal that are believed to underlie the heightened vulnerability to relapse: conditioned responses of norepinephrine A1/A2 neuron release in the extended amygdala and changes in the mesocorticolimbic dopamine system and its afferents that alter hedonic processing. At the same time, motivation or learning for drug reward and drug- associated cues is increased [110]. Abstinence from chronic drug use unmasks neuroadaptation in brain function that contributes to an ill-defined feeling of dysphoria, anxiety, or malaise that can only be alleviated by renewed administration of the drug. Continued drug use is rewarding because it stimulates the natural reward circuitry and also because the action offsetting the anti-reward response (stress hypersensitivity and anxiety) produces an additional reinforcing effect that increases the sum of positive reinforce- ment. The protracted withdrawal period is often characterized by elevated anxiety involving alterations in the noradrenergic input to the bed nucleus of the stria terminalis or amygdala. Drug-associated stimuli activate noradrenergic A1/A2 neurons during protracted withdrawal, leading to elevated anxiety through the ensuing release of noradrenergic neurons in the extended amygdala. In turn, additional reinforcing properties are produced via the alleviation of anxiety when these norad- renergic neurons are inhibited, reflecting negative reinforce- ment [110; 111]. Additionally, chronic drug exposure results in a generalized hedonic deficit for natural rewards and an incentive value for drugs. This deficit in the capacity for obtaining reinforcement from non-drug sources generates symptoms such as anhedonia and depression [111]. The sensitized hedonic drug value is also believed to increase motivation for drug use. Furthermore, the changes that occur in hedonic processing mechanisms follow- ing chronic opioid exposure may involve multiple systems that recover at different rates. Changes in the afferents to the ventral tegmental area or in plasticity within the ventral tegmental area itself could play a vital role in altered hedonic processing during protracted withdrawal [110; 111]. Taken together, these findings suggest that elevated drug seeking during protracted withdrawal may involve two pro- cesses: prolonged and elevated anxiety leading to a negative reinforcement mechanism for opioids and increased incentive motivation for drug reward through a sensitization mechanism [110; 111]. LIABILITY OF MISUSE OF LEGITIMATELY PRESCRIBED OPIOID DRUGS There is broad consensus that patients with acute and chronic pain have often received inadequate pain control out of a fear of creating dependence. This is typified by the results of a survey in which 35% of Canadian family physicians reported they would never prescribe opioids for moderate-to-severe chronic pain and 37% identified dependence as a major
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MDRI2026
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