Nora Volkow on why opioids are unique

Nora Volkow on MAT, naloxone, new drugs, and why opioids are unique – Opioid Watch – Nonprofit News from The Opioid Research Institute – July 2018

This is part 2 (part 1 here) of an interview with research psychiatrist Nora Volkow, MD, the director of the National Institute on Drug Abuse for the past 15 years.

  • Q: You are a pioneer in the use of brain scans to study addiction. At the level of brain chemistry, how is opioid addiction similar to other addictions, and how does it differ?

Addictive drugs can orchestrate a state of positive affect, an experience that, for some people, can be more powerful and/or compelling than that produced by natural rewards, like food or sex.  

Though various drugs trigger this by distinct pharmacological mechanisms, all of them trigger fast and large dopamine increases in the nucleus accumbens, which is the main reward center in the brain.

The dopamine neurons that project to the nucleus accumbens are part of an evolutionary conserved brain network whose main purpose is to help fine tune goal-directed behaviors by encouraging repeating pleasurable ones, that supposedly increase selective advantage, and avoiding ones that are aversive.

The large, drug-induced spikes in dopamine trigger conditioned learning by which the reward experience from the drug is associated to whatever cues, emotions and behaviors that happened to be linked with that experience.

With repeated drug exposure, conditioned learning boosts the odds of repeating the experience and, with time, these conditioned cues by themselves will generate the desire for the drug (craving).

Here, she is supporting the view of Maia Szalavitz, who has shown that addiction is a kind of learning disorder or learning disability. (see Can You Get Over an Addiction?)

In parallel, repeated activation of the dopamine system leads to downregulation [i.e. reduction] of dopamine signaling in between periods of drug consumption that further contributes to drug taking to compensate for this deficit.

Opioids, like other drugs, increase dopamine in the nucleus accumbens, but they do not do so directly. In contrast to stimulant drugs like cocaine, they do so by “releasing the brakes” on dopamine release.

Specifically, the rewarding effects of opioids are mediated by the mu opioid receptors, which are located in many brain cells, including those that inhibit dopamine neurons.

Thus opioids increase dopamine by disinhibiting dopamine neurons.

Also, similar to other drugs, their repeated exposure results in a downregulation of dopamine D2 receptors in the brain which are necessary for dopamine signaling.

Opioids are among the most addictive of the drugs of abuse.

They produce the greatest levels of tolerance (triggering adaptations that require increasing doses to achieve similar effects) and physical dependence (adaptations that trigger painful and complex physical withdrawal symptoms when the drug is abruptly discontinued).

Actually, this is true of alcohol as well.

Even she (NIDA) talks about this great variety of tolerance, it seems all other government agencies and legislatures believe there should be “standard doses” of opioids.

These features make chronic users much more likely to escalate their use and repeat use to mitigate or avoid the intense withdrawal symptoms. Repeated opioid use also triggers a very severe disruption of mood that can lead to depression/dysphoria and anxiety and that also contributes to relapse and drug taking.

However, I still believe that opioid medication is “used up” as it stifles ongoing pain when our endogenous opioids are depleted at such a rate that our bodies cannot produce enough of them.

That’s just my theory and it’s not scientific, but many of my previous “hunches” about how my own broken body (EDS) works have been proven true over the decades.

After reading about and experiencing so many blatant lies from our medical “providers” (opioids make you addicted, the law says I can’t prescribe more opioids, opioids make you dull and dopey…), I have more faith in my own thinking than I do in them.

At least I stay up to date by reading about the latest developments to continually expand my knowledge and I research the conditions and medications that are pertinent for me, whereas doctors rarely have enough time for this.

  • Q: I’ve read some accounts of naloxone not working as well to reverse fentanyl overdoses as other kinds of opioid overdose. Are those reports accurate and, if so, what sorts of innovations might help?

It is difficult to draw solid conclusions in this regard because the situation is evolving so rapidly and there are confounding factors to overdose treatment beyond the drug itself.

Naloxone, an opioid receptor antagonist, is very effective at reversing overdoses. But bystanders may not reach the person in time and the usual doses given may not be powerful or long-lasting enough to reverse overdoses of fentanyl or other highly potent synthetic opioids.

Thus, while naloxone is the standard drug for fentanyl overdose rescue, attempts to revive patients with naloxone could indeed be unsuccessful, due to the rapid onset of fentanyl’s action.

However, we can find studies where naloxone has been found to be rather effective, like a recent analysis (see here) of over 1,000 cases of uncomplicated, presumed fentanyl overdoses treated in an emergency department, most of whom survived and could be discharged after brief observation.

There are increasingly worrisome challenges (see here) that we need to address, like the variable potency of opioid formulations due to erratic adulteration of the drug supply with synthetic opioids (possibly changing the efficacy of standard naloxone formulations for overdose rescue), potentially shorter overdose response times, and reports of fentanyl exposure among people who use drugs but have never taken opioid

Also, opioids are frequently consumed with other drugs, some of which have respiratory depressant effects such as alcohol and benzodiazepines, which are not reverted by naloxone.

As the fentanyl problem is growing, there is an urgent need for new, effective harm-reduction strategies and technologies, as well as overdose reversal

We must also develop better strategies to effectively engage people who have overdosed in addiction treatment.

  • Q: What is the most exciting research you’re aware of concerning new pharmaceuticals or therapies to treat pain—especially chronic pain?

In the short term, I think an important realization is that opioids should not be the first line of treatment for chronic pain outside of active cancer treatment, palliative care, and end-of-life care. This highlights the need for alternative safer analgesics.

I haven’t heard of any cases where opioids were given as the first treatment for chronic pain. The only situation in which opioids are given first is after surgery.

NIDA has initiated multiple strategic partnerships to advance development of medications for pain, including academic institutions, pharmaceutical and biotechnology companies, private and public foundations, and small businesses.

This includes research to identify new pain medicines with reduced abuse, tolerance, and dependence risk, as well as devising alternative delivery systems (see  and formulations for existing drugs that minimize diversion and non-medical use (e.g., by preventing tampering) and reduce the risk of overdose deaths.

We don’t need to spend all this money on finding new pain medicine because the crisis is about addiction, not the specific drug.

In fact, most overdoses are from a mixture of several drugs. Single-drug overdoses are extremely rare.

Researchers are working to develop a new generation of safer medications for acute or severe pain.

Some of these target the opioid receptor but focus on development of opioid drugs that

  • have biased agonist properties,
  • bind to truncated opioid receptors,
  • rely on peripheral opioid receptors or
  • that boost the natural endogenous opiate system,

which should minimize their untoward effects.

Others rely on alternative neurotransmitters that modulate pain as is the case for drugs that target the endogenous cannabinoid system, which include

  • purified cannabinoids (see here),
  • positive allosteric modulator (see here) of the cannabinoid-type 1 receptor, or
  • drugs that interfere with the degradation of endogenous cannabinoids.

Others target molecules to interfere with the conductance of pain signals by blocking Na, K or Ca channels.

Still others act by interfering with immune molecules that are responsible for pain generation.

Research is also ongoing on peripheral and transcranial brain stimulation for management of chronic pain.

A fascinating recent study (see here) showed that opioids (endogenous peptides and drugs) signal not only when bound to membrane opioid receptors, but also when these receptors are internalized in the cells.

However, the study showed that intracellular signaling differed between endogenous peptides and drugs and these differences might help us understand why tolerance develops rapidly for drugs but not for endogenous peptides and might also help guide the design of pain relievers that do not produce addiction.

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