All brain diseases have some form of behavioral expression—Alzheimer's disease expresses itself as memory loss, schizophrenia expresses as unusual mood changes—and opioid dependence expresses itself as a compulsion to use opioids.^1,3

The fact that a portion of opioid-dependent patients originally chose to misuse opioids does not make their condition any less the result of disease. Patients' choices (eg, regarding diet, exercise) contribute to the onset or severity of several chronic diseases, including hypertension, CHD, and diabetes.⁴

Furthermore, while the initial choice to use opioids may have been voluntary, once opioid dependence develops, use is compulsive—not voluntary.⁵

Provoking Change
The pervasive changes to brain structure and function that distinguish opioid dependence are, without exception, preceded by chronic opioid use. However, chronic opioid use is only one factor in the etiology of this disease, and, by itself, will not cause opioid dependence.^3,6

Mu receptors in the brain adapt to repeated opioid exposure by becoming opioid tolerant. Tolerance is recognized as a symptom of opioid dependence, but absent of any other identifying symptoms, it is indicative only of physical dependence on opioids.^3,6

The neurological changes that produce opioid tolerance and physical dependence are well understood. These changes appear to correct themselves within a period of weeks following cessation of opioid use.³

The Same, but Different
By contrast, the cluster of symptoms recognized as opioid dependence results from neurological changes that are wider ranging and significantly more complex.³ These neurological changes do not reverse themselves shortly after opioid use has ceased, but often persist for extended lengths of time.²

The hallmark of opioid dependence—compulsive drug seeking and use—stems in large part from powerful opioid cravings brought about by these complex changes.⁷

Both opioid craving and opioid withdrawal frequently drive patients' drug seeking and use.³

However, only opioid cravings are tied to compulsive drug-seeking and use. Furthermore, cravings can compel compulsive opioid use independently of the presence of withdrawal symptoms or physical dependence on opioids.⁷

The uncontrollable drug consumption seen with opioid dependence is primarily driven by opioid cravings. This strong correlation between cravings and compulsive drug use is an inherent part of why opioid craving (but not opioid withdrawal) is considered a definitive feature of opioid dependence.⁷

The biological basis of drug cravings is not entirely understood much beyond the generally accepted notion that cravings are an adverse consequence of repeated activation of the brain's reward circuit initially stemming from chronic opioid use.^3,7

One of the theories put forward to explain cravings posits that, over time, opioid's constant activation of the reward circuit alters neurological functioning along those pathways causing them to become "hypersensitized" to both the direct effects of opioids and to the environmental cues associated with their use (ie, triggers). This hypersensitized reward circuit causes "pathologic" cravings for opioids even in response to moderate stimulation.⁷

Sensitivity to opioid cravings is typically one of the most persistent symptoms of opioid dependence. This persistence is attributable to the comparatively prolonged time required for the opioid-dependent brain to restore some degree of predisease normalcy.² For this reason, opioid-dependent patients may be vulnerable to drug cravings (and relapse) for months and even years after their last opioid use.⁷