Addiction Not a Predictable Result of Opioid Prescribing

Addiction is not a predictable result of opioid prescribing – NEJM – Mar 2016 – Nora D. Volkow, M.D.,  and A. Thomas McLellan, Ph.D.

Anti-opioid crusaders in the media insist that any opioid medications can almost immediately cause addiction in any person exposed to them.

However, as head of NIDA (the National Institute on Drug Abuse at the NIH), Dr. Volkow has more expertise in addiction than the self-anointed “experts” broadcasting false narratives about opioid addiction (and often trying to sell addiction-recovery programs). Dr. Volkov makes very clear the differences between dependence, tolerance, and addiction.

There is lingering misunderstanding among some physicians about the important differences between physical dependence and addiction.  

The repeated administration of any opioid almost inevitably results in the development of tolerance and physical dependence.

These predictable phenomena reflect counter-adaptations in opioid receptors and their intracellular signaling cascades.

These short-term results of repeated opioid administration resolve rapidly after discontinuation of the opioid (i.e., in a few days to a few weeks, depending on the duration of exposure, type of opioid, and dose).

In contrast,

addiction will occur in only a small percentage
of patients exposed to opioids.

Addiction develops slowly, usually only after months of exposure, but once addiction develops, it is a separate, often chronic medical illness that will typically not remit simply with opioid discontinuation

The molecular processes responsible for addiction are also distinct from those underlying tolerance and physical dependence, and so are the clinical consequences.

Tolerance leads to a decrease in opioid potency with repeated administration. Thus, prescribing opioids long-term for their analgesic effects will typically require increasingly higher doses in order to maintain the initial level of analgesia — up to 10 times the original dose.

In particular, tolerance to the analgesic and euphoric effects of opioids develops quickly, whereas tolerance to respiratory depression develops more slowly,

Physical dependence underlies the physiological adaptations that are responsible for the emergence of withdrawal symptoms on the abrupt discontinuation of opioids.

In the context of chronic pain management, the discontinuation of opioids requires dose tapering in order to prevent the emergence of such withdrawal symptoms.

Unlike tolerance and physical dependence,

addiction is not a predictable result
of opioid prescribing.

Addiction occurs in only a small percentage of persons who are exposed to opioids — even among those with preexisting vulnerabilities.

Older medical texts and several versions of the Diagnostic and Statistical Manual of Mental Disorders (DSM) either overemphasized the role of tolerance and physical dependence in the definition of addiction or equated these processes (DSM-III and DSM-IV).

However, more recent studies have shown that the molecular mechanisms underlying addiction are distinct from those responsible for tolerance and physical dependence, in that they evolve much more slowly, last much longer, and disrupt multiple brain processes.

Cardinal features of addiction include

  • a pronounced craving for the drug,
  • obsessive thinking about the drug,
  • erosion of inhibitory control over efforts to refrain from drug use, and
  • compulsive drug taking (DSM-5).

These characteristics aren’t seen in patients taking opioids only to treat legitimate pain. When my pain is under control, I don’t think about opioids, I don’t crave them, and I don’t take more.

Pain patients are usually prescribed a quantity of opioids deemed sufficient for a full 30 days, so we cannot lose our “inhibitory control” and refrain from excessive drug use without jeopardizing the very real pain relief we need for the rest of the month.

These behavioral changes in turn are associated with structural and functional changes in the reward, inhibitory, and emotional circuits of the brain.

Clinical studies have also shown that the ability of opioids to produce addiction is genetically modulated, with heritability rates similar to those of diabetes, asthma, and hypertension.

For these reasons, we do not know the total dose or the duration of opioid administration that will reliably produce addiction.

This is just another way of saying that addiction is not (and cannot be) a predictable result of exposure to opioids.

See also Addiction, Dependence, and Tolerance, which contains further references and explanations.

However, we do know that the risk of opioid addiction varies substantially among persons, that genetic vulnerability accounts for at least 35 to 40% of the risk associated with addiction

In a person with an opioid addiction, discontinuation of the opioid will rapidly reverse the tolerance and physical dependence within days or a couple of weeks

In contrast, the underlying changes that are associated with addiction will persist for months and even years after the discontinuation of opioids.

This finding is clinically relevant, because after abstinence from opioids, addicted patients are particularly vulnerable to overdosing: their intense drive to take the drug persists, but the tolerance that previously protected them from overdosing is no longer present.

These effects explain the high risk of overdosing among persons with an opioid addiction after they have been released from prison or from a detoxification program.

This article also explains how opioids bind to receptors located all through our bodies:

Opioid medications exert their analgesic effects predominantly by binding to mu-opioid receptors.

Mu-opioid receptors are densely concentrated in brain regions that regulate pain perception (periaqueductal gray, thalamus, cingulate cortex, and insula), including pain-induced emotional responses (amygdala), and in brain reward regions (ventral tegmental area and nucleus accumbens) that underlie the perception of pleasure and well-being.

This explains why opioid medications can produce both analgesia and euphoria.

I would debate whether legitimate opioids at doses not in excess of what is needed to relieve pain produce euphoria in patients: Opioids, Endorphins, and Getting High

Mu-opioid receptors in other brain regions and in peripheral organs account for other common opioid effects.

In particular, mu-opioid receptors in the brain stem are mainly responsible for the respiratory depression associated with opioid-overdose incidents and deaths. (Figure 1).

Figure 1. Location of Mu-Opioid Receptors.

Shown are the locations of mu-opioid receptors in the human brain, with high concentration

  • in the thalamus, periaqueductal gray, insula, and anterior cingulate (regions involved with pain perception),
  • in the ventral tegmental area and nucleus accumbens (regions involved with reward),
  • in the amygdala (a region involved with emotional reactivity to pain), and
  • in the brain stem (nuclei that regulate breathing).

In the spinal cord, a high concentration of mu-opioid receptors is located in the dorsal horn.

Mu-opioid receptors in peripheral terminals modulate the perception of pain, and receptors in the small intestine regulate gut motility.

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