Biologically, opioid addiction can be understood in terms of neuroadaptations that arise when exogenous opioids are taken continuously and long-term.1 Tolerance and dependence are 2 such central adaptations. Tolerance is the need to increase dose to achieve the same effect, and dependence is the physiologic response either to an uncompensated increase in tolerance or to the withdrawal of a drug.2 Tolerance may develop for both the euphoric and the analgesic effects of opioids and can be produced by psychological as well as pharmacological factors. Dependence is manifest as withdrawal symptoms (eg, sweating, anxiety, insomnia) that are caused by rebound at central noradrenergic nuclei, and the less well-understood effects of hyperalgesia (increased pain sensation) and anhedonia (inability to feel pleasure).3,4 Withdrawal hyperalgesia and anhedonia may explain the worsening of pain and mood that is seen during an opioid taper or after detoxification. Withdrawal symptoms are powerful drivers of opioid seeking, which in turn can be induced by factors that change tolerance (Figure). Addiction is further defined by aberrant opioid-seeking behaviors that, when persistent, result in irreversible changes in the brain.1
Register and get free email Table of Contents alerts, saved searches, PowerPoint downloads, CME quizzes, and more
Subscribe for full-text access to content from 1998 forward and a host of useful features
Activate your current subscription (AMA members and current subscribers)
Purchase Online Access to this article for 24 hours
Figure. Interdependence of mood, tolerance/dependence, and pain. Even in normal individuals, pain and mood are interdependent, in part through endogenous opioid mechanisms. Individuals who are taking exogenous opioids continuously over the long-term adapt by developing tolerance and dependence. Psychological factors can alter tolerance and thereby induce withdrawal symptoms. For the dependent individuals, the need for more opioids becomes the predominant reaction to stress. Although pain is seen as the primary reason to dose escalate, this pain is augmented by psychosocial stressors.
Thank you for submitting a comment on this article. It will be reviewed by JAMA Internal Medicine editors. You will be notified when your comment has been published. Comments should not exceed 500 words of text and 10 references.
Do not submit personal medical questions or information that could identify a specific patient, questions about a particular case, or general inquiries to an author. Only content that has not been published, posted, or submitted elsewhere should be submitted. By submitting this Comment, you and any coauthors transfer copyright to the journal if your Comment is posted.
* = Required Field
Disclosure of Any Conflicts of Interest*
Indicate all relevant conflicts of interest of each author below, including all relevant financial interests, activities, and relationships within the past 3 years including, but not limited to, employment, affiliation, grants or funding, consultancies, honoraria or payment, speakers’ bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued. If all authors have none, check "No potential conflicts or relevant financial interests" in the box below. Please also indicate any funding received in support of this work. The information will be posted with your response.
Some tools below are only available to our subscribers or users with an online account.
Download citation file:
Web of Science® Times Cited: 4
Customize your page view by dragging & repositioning the boxes below.
More Listings atJAMACareerCenter.com >
All results at
and access these and other features:
Enter your username and email address. We'll send you a link to reset your password.
Enter your username and email address. We'll send instructions on how to reset your password to the email address we have on record.
Athens and Shibboleth are access management services that provide single sign-on to protected resources. They replace the multiple user names and passwords necessary to access subscription-based content with a single user name and password that can be entered once per session. It operates independently of a user's location or IP address. If your institution uses Athens or Shibboleth authentication, please contact your site administrator to receive your user name and password.