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Nora Volkow on MAT, naloxone, new drugs, and why opioids are unique
By ROGER PARLOFF|July 23, 2018
NIDA Director Nora Volkow at TEDMED in 2014.
TEDMED
Quick Takeaway
  • "A great part of the tragedy of this opioid epidemic is that ... we already possess effective treatment options ... yet tens of thousands of people die each year because they have not received these treatments."
  • "The main problem is that ... misperceptions that methadone and buprenorphine 'substitute a new addiction for an old one' persist."
  • "We should not waste time and resources on strategies that have not been validated as effective by a rigorous scientific evaluation."

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

In Part 1, she addressed controversies surrounding the degree to which, as the epidemic matures, prescription opioids should remain the focus of our concern, and whether the pendulum has now swung too far, making it too difficult for chronic pain patients to obtain their medications.

Here, in part 2, she addresses the challenge of getting more people with opioid addiction into medication-assisted treatment; the most promising research projects relating to addiction and pain; whether naloxone is effective at reversing fentanyl overdose; and what it is, in terms of brain science, that makes opioids unique among addictive drugs. (Parenthetical links are to citations provided by Volkow.)

Nora Volkow, MD, in June 2013. (Photo: Mary Noble Ours)

How far have we come in terms of improving the availability and use of medication-assisted treatment for opioid addiction? What are the most important barriers to our doing better? What steps can we take?

We have made a lot of progress but the treatment gap is still huge. The main problem is that, while receiving an agonist medication for maintenance is pharmacodynamically distinct from sustaining an addiction to prescription analgesics or illicit opioids, misperceptions that methadone and buprenorphine “substitute a new addiction for an old one” persist.

Even where maintenance medications are used, they are often prescribed for too short a time or at too low a dose. According to SAMHSA, nearly half of patients receiving buprenorphine in opioid treatment facilities receive 90 days or fewer of continuous treatment with this medication. This shows that many providers are simply not following evidence-based practices.

“We should not waste time and resources on strategies that have not been validated as effective by a rigorous scientific evaluation.”

There are several strategies that could increase medication-assisted treatment (MAT) delivery to those with OUD [opioid use disorder] (beyond the obvious need of reducing the stigma and increasing the public’s understanding of MAT for OUD). They include increasing adherence with access to extended-release formulations, increasing access to MAT in criminal justice settings, providing MAT in primary care and specialty care (i.e., emergency departments, pain and infectious clinics), using telehealth and other models of care to prescribe and monitor MAT in rural areas or those without providers, and allowing pharmacists to administer MAT.

Should the US continue to fund opioid treatment facilities that do not provide medication-assisted treatment?

This is a policy decision that would not be appropriate for me to weigh on directly. I can say however that, in general, we should harness the power of every evidence-based approach to stem the tide of this devastating and costly epidemic and that we should not waste time and resources on strategies that have not been validated as effective by a rigorous scientific evaluation.

Nora Volkow on prescription opioids, chronic pain and ‘hype’

A great part of the tragedy of this opioid crisis is that, unlike in previous such crises America has seen, we already possess effective treatment options that could address it and save many lives, yet tens of thousands of people die each year because they have not received these treatments. Thus, expanding access to medications for OUD is essential if we are to reverse these trends. Ending the crisis will require changing policies to make these medications more accessible and educating primary care and emergency providers, among others, that opioid addiction is a medical illness that must be treated aggressively with the effective tools that are available.

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.

NIDA Director Nora Volkow in August 2017 (Photo: National Institute on Drug Abuse)

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).

“Opioids are among the most addictive of the drugs of abuse and also produce the greatest levels of tolerance and physical dependence.”

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). 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.

This Spring, Congress gave NIH an additional $500 million to invest in science targeted at alleviating the opioid crisis. What research is most exciting to you in terms of new drugs or therapies for treating addiction?

Thanks to the funding boost by Congress, NIH has been able to nearly double funding for research on opioid misuse/addiction and pain, from approximately $600 million in fiscal year 2016 to $1.1 billion in fiscal year 2018, which will significantly enhance other government-wide efforts. The HEAL (Helping to End Addiction Long-term) Initiative (see here), is the NIH’s signature program in this area that has been launched as an aggressive, trans-agency effort to speed scientific solutions to stem the national opioid public health crisis. This initiative will bolster research across the NIH in the areas of both pain and opioid use disorders.

Nora Volkow, MD, in 2017. (Photo: National Institute on Drug Abuse)

A specific goal is to accelerate development of therapeutics for the management of pain and of opioid use disorder, including medications. Priorities also include implementation research to develop models that can expand the use of medications for the treatment of opioid use disorders in healthcare and criminal justice settings and in difficult to reach communities because of remoteness and lack of infrastructure.

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.

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

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. Overdoses of fentanyl should be treated immediately with naloxone and may require higher doses to successfully reverse the overdose (see here and JR. R. InFocus: Acetyl Fentanyl., Emerg Med News 2013: 35: 1) or repeated dosing once the first dose wears off, which could precipitate a new overdose.

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 opioids. 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. Naloxone programs must be scaled up and adapted to constantly changing environments; we also need to improve the standards for post-overdose care, and integrate new technologies (see here) to detect overdose and deliver naloxone.

Research is also needed to develop technologies that can detect an overdose and signal for help, as well as intervene automatically to stimulate respiration. We must also develop better strategies to effectively engage people who have overdosed in addiction treatment.

But in addition to new or differently formulated antagonists of the mu-opioid receptor, other targets such as the 5HT1A receptor (a serotonin receptor subtype) or ampakines may hold promise as alternative ways of reversing respiratory depression caused by opioid overdose by itself or in combinations with other drugs (see here]). 

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.

“A partnership is working to develop an abuse deterrent opioid formulation that uses product technology—attaching an extension to the opioid molecule that renders it inactive if injected, snorted, or smoked.”

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 and formulations for existing drugs that minimize diversion and non-medical use (e.g., by preventing tampering) and reduce the risk of overdose deaths.

For example, a partnership is working to develop an abuse deterrent opioid formulation that uses product technology—attaching an extension to the opioid molecule that renders it inactive if injected, snorted, or smoked; instead it must pass through the digestive system to begin the process of releasing the opioid. Early phase trials have supported safety, dose proportionality, and a clinically beneficial extended release profile. [See also here.]

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.

Filed under: Addiction/ Q&A/ Research/ Treatment