JH Waggoner Chair and Professor of Psychiatry, Pharmacology, Immunology, and Neuroscience;  Director, Section of Alcohol & Addiction Psychiatry, Baylor College of Medicine, Houston, Texas

Thomas R. Kosten, MD

The question: Why don't we hear about the opioid crisis in America anymore? Did it go away during COVID?

This week, Thomas R. Kosten, MD, takes on the question about opioids in the US.

is the Jay H. Waggoner Endowed Chair and co-founder at the Institute for Clinical and Translational Research. He is also a professor of psychiatry, neuroscience, pharmacology, and immunology at Baylor College of Medicine in Houston, Texas.

Videos

Did the opioid crisis go away during COVID-19? Or has it gotten worse? 

Opioid Crisis Awareness

Overdose awareness day, which occurs on August 31, raises particular concerns about substances adulterated with illicitly manufactured fentanyl, which has spread from being the 

major cause of not only overdoses from opioids, but also from nonopioids

 Look-alike versions of other prescription opioids (Percocet), benzodiazepines (Valium), and stimulants (Adderall) have been imported to the United States’ illicit drug markets and they often contain toxic or lethal doses of fentanyl. Moreover, even during the COVID-19 pandemic when the volume of drug screens dropped significantly, those tested showed a 

marked increase in urine drug screens positive for illicit fentanyl 

(35%), and more strikingly for methamphetamine (89%), which heralded the fourth wave of the opioid epidemic with combined stimulants and opioids.

 Because of the increasing morbidity and mortality from this combination of stimulants and fentanyl, neither of which have effective or pharmacotherapies approved by the US Food and Drug Administration, therapeutic strategies have expanded to include immunization with vaccines.

A History of Vaccines for Substance Use Disorder

Vaccines for addictive substances were first conceptualized in the late 1960s, based on introducing a foreign substance (ie, heroin) to induce T-cells and B-cells to make antibodies against the substance. Once the individual has antibodies, using the drug would lead to the formation of a drug-antibody complex that can be excreted rather than crossing the blood brain barrier and producing psychoactive effects. 

 of substantial portions of any amount of the drug taken. That 

 limits the drug’s reinforcing properties.

 faced the problem of being too small to generate an antibody response. To address this size problem, the drugs must be conjugated to an immunogenic carrier protein (eg, cholera toxin, keyhole limpet hemocyanin (KLH), tetanus toxoid) and mixed with an adjuvant such as alum to enhance the immune response. Still, these 

 have struggled to produce sufficient levels of antibodies and have a high affinity for the free drug. To date, a 

 using different combinations of adjuvants and carrier proteins to increase the magnitude, affinity, and durability of antibodies, as well as reduce the substantial variability among individuals in the magnitude of their antibody responses.

With this background on anti-addiction vaccines, we faced the start of the 

 in the 1990s with the introduction of oxycodone (OxyContin) by Purdue Pharma. Over the past 20 years we have undergone 

. In the late 1990s, overdose deaths rose due to prescription opioids, transitioning to the second wave of heroin overdoses in 2010. The third wave of deaths began in 2013 with illicitly manufactured synthetic opioids, particularly fentanyl and fentanyl analogs. More recently, a fourth wave has begun with the combination of fentanyl disguised in counterfeit opioid, sedative, and stimulant pills looking like the marketed pharmaceutical products. In 2019,

 over 36,000 deaths involved synthetic opioids

, accounting for nearly 73% of all opioid-related deaths that year. In the 12 months leading up to May 2020, deaths due to fentanyl increased 38.4% compared to the previous year with many of those overdoses in combinations with sedatives and stimulants.

An ideal vaccine would induce antibodies specific to the misused opioids (eg, fentanyl) while allowing for medical interventions with other classes of opioids when necessary. In a study by Kosten et al, the morphine vaccine KLH-6-SM (6-succinylmorphine linked to lysine groups on KLH) attenuated morphine-induced behavioral responses in rats. Vaccinated rats also showed a 

 diminished heroin reward and heroin-induced drug-seeking, and vaccinated rats required significantly higher doses of heroin for analgesia.

 against oxycodone prevented oxycodone-induced analgesia and respiratory depression in vaccinated rats with minimal cross-reactivity to methadone, buprenorphine, and opioid antagonists.

Vaccines against fentanyl are now of particular interest because our well-established treatments of methadone, buprenorphine, and naltrexone do not block fentanyl, and because the adulteration of other substances with fentanyl has led to a rapid increase in overdoses among unwitting users. Because 

fentanyl is 50 to 100 times more potent than morphine

, the lethal dose is very small at approximately 2mg and even at 1000 times smaller doses for fentanyl analogs.

 Therefore, vaccines against fentanyl may be particularly effective because the concentration of antibodies needed is much lower than concentrations needed for blocking other 

 have shown promising results for overdose prevention as vaccinated animals required much higher doses of fentanyl for analgesic and respiratory depressant effects.

Anti-fentanyl vaccines combined with methadone, buprenorphine, or naltrexone will likely be highly successful because increasing the fentanyl dose sufficiently is unrealistic in human use due to the antibody levels appearing to be 100 or more times greater than the lethal blood levels of fentanyl found in overdoses. These anti-fentanyl vaccines will be life-saving adjuncts to opiate agonist treatments and provide complete overdose protection from fentanyl and its derivatives, against which current treatments cannot protect.

Researchers have made significant progress in vaccine development for substance use disorder, and now have a more comprehensive understanding of vaccine design, as well as human behavior after vaccination. Despite the success of several vaccines in animal studies, the ones advancing to human clinical trials against cocaine and nicotine failed to demonstrate efficacy against placebo. Even at adequate antibody titers for typical abused doses, cocaine users can increase their use to compensate for the blockade, and clearly intrinsic personal motivation for abstaining is essential for most vaccines to be helpful in maintaining abstinence. The introduction of the stronger, more lethal fentanyl has rekindled interest and persistence in improving vaccines as we aim to minimize toxicity and prevent overdose from fentanyl.

1. National Institute on Drug Abuse. Overdose death rates. 2021. Accessed August 9, 2021. 

https://www.drugabuse.gov/drug-topics/trends-statistics/overdose-death-rates

2. Niles JK, Gudin J, Radcliff J, Kaufman HW. 

The opioid epidemic within the COVID-19 pandemic: drug testing in 2020.

The rate hypothesis and agonist substitution approaches to cocaine abuse treatment. 

4. Abreu ME, Bigelow GE, Fleisher L, Walsh SL. 

Effect of intravenous injection speed on responses to cocaine and hydromorphone in humans.

The continuing search for an addiction vaccine.

Current status and future prospects for the development of substance abuse vaccines.

Current status of immunotherapies for addiction. 

8. O’Donnell JK, Gladden RM, Seth P. Trends in deaths involving heroin and synthetic opioids excluding methadone, and law enforcement drug product reports, by census region — United States, 2006–2015. Centers for Disease Control and Prevention. September 1, 2017. Accerssed August 9, 2021. 

https://www.cdc.gov/mmwr/volumes/66/wr/mm6634a2.htm

9. Mattson CL, Tanz LJ, Quinn K, et al. Trends and geographic patterns in drug and synthetic opioid overdose deaths — United States, 2013–2019. Centers for Disease Control and Prevention. February 12, 2021. Accerssed August 9, 2021. 

https://www.cdc.gov/mmwr/volumes/70/wr/mm7006a4.htm

10. National Center for Health Statistics. Provisional drug overdose data. 2021. Accessed August 9, 2021. 

https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm

11. Kosten TA, Shen XY, O’Malley PW, et al. 

A morphine conjugate vaccine attenuates the behavioral effects of morphine in rats.

Prog Neuropsychopharmacol Biol Psychiatry

12. Schlosburg JE, Vendruscolo LF, Bremer PT, et al. 

Dynamic vaccine blocks relapse to compulsive intake of heroin.

13. Raleigh MD, Peterson SJ, Laudenbach M, et al.

 Safety and efficacy of an oxycodone vaccine: addressing some of the unique considerations posed by opioid abuse.

A review: fentanyl and non-pharmaceutical fentanyls.

15. Bremer PT, Kimishima A, Schlosburg JE, et al. 

Combatting synthetic designer opioids: a conjugate vaccine ablates lethal doses of fentanyl class drugs.

16. Tenney RD, Blake S, Bremer PT, et al. 

Vaccine blunts fentanyl potency in male rhesus monkeys.

17. Stone AE, Scheuermann SE, Haile CN, et al. 

Fentanyl conjugate vaccine by injected or mucosal delivery with dmLT or LTA1 adjuvants implicates IgA in protection from drug challenge.

Articles

Manufactured fentanyl is a major cause of overdoses for opioids and nonopiods. Can a vaccine immunize against overdose? 

Anti-Fentanyl Vaccines as Medical Solutions to Overdose Deaths

This Special Report contains articles about cannabis use and its potential complications, including 

 highlights the use of cannabinoids among the geriatric population. Cannabis and cannabidiol (CBD) use in older adults has become more prevalent as a result of reduced stigma; leniency in state restrictions on possession and sale; and advertisements touting benefits for chronic pain, peripheral neuropathy, stress, anxiety, depression, insomnia, headaches, and the adverse effects of chemotherapy. Medical marijuana use by individuals 65 and older has increased more than 8-fold in recent years. The article nicely summarizes how heavy marijuana use can cause mild functional and structural brain impairments, affecting attention, processing speed, motor coordination, verbal memory, and executive function. Overall, every 

, along with their caregivers, should be queried as to their use of cannabis products. They should also be cautioned that those with preexisting neurocognitive impairment, such as Alzheimer disease, might be particularly vulnerable to adverse effects such as drowsiness, dizziness, fatigue, and mood changes.

Clinical Management of Cannabis Complications


Thomas R. Kosten, MD, and Christopher D. Verrico, PhD

The Age of Cannabis Has Arrived: Issues for Older Adults

Cannabis 2021: What Clinicians Need to Know

Cannabis and Psychosis: A Synthesis of Quantitative Reviews

How to Discuss Cannabis With Your Patients

You Spoke, We Listened. Psychiatry's Cannabis Survey

We have a changing cultural ethos regarding cannabis acceptability; nevertheless, many users will suffer from its use. Some will develop CUD, and many can damage their educational achievement, work lives, health, and relationships. The 

 about the increasing number of cannabis users who experience negative effects, ranging from the annoying to the catastrophic. As noted, these effects arise from 3 sources: potential users’ sharply decreased perception of risk in recent years, easy availability of cannabis, and increased potency of Δ-9-tetrahydrocannabinol (THC) in legal and illegal cannabis sources. In recent years, THC concentrations in smoked cannabis doubled to 17.1% in 2017. Due to these high THC concentrations, clinicians need to recognize psychiatric complications of heavy repeated cannabis use, such as depression, anxiety, psychosis and, although rare, the cannabinoid hyperemesis syndrome.

Furthermore, although subtle compared with alcohol or opioid withdrawal, cannabis withdrawal does occur and includes irritability, anxiety, depression, insomnia, disturbing dreams, anorexia, abdominal pain, tremors, sweating, fever, chills, headache, and craving. Off-label use of medications for withdrawal are suggested and might include gabapentin and the THC analogue dronabinol, and limited amounts of benzodiazepines to relieve anxiety and insomnia. However, there has been little efficacy in the treatment of CUD.

 focuses on patients with schizophrenia. It synthesizes the large literature on cannabis and psychosis risk. The piece also reviews the literature on genetic associations, earlier age of onset, poorer treatment outcomes, and cognition. For example, a critical meta-analysis found an association between better cognitive performance and cannabis use in schizophrenia, a finding that merits careful replication because another analysis of first-episode schizophrenia found patients with psychosis and current cannabis use had significantly lower premorbid and current IQ scores.

We hope that you find that this educational 

 enhances your understanding of the rapidly changing field of cannabinoids and their clinical implications, particularly for our geriatric population and patients with schizophrenia.

is the Jay H. Waggoner Endowed Chair and co-founder at the Institute for Clinical and Translational Research. He is also a professor of psychiatry, neuroscience, pharmacology, and immunology at Baylor College of Medicine in Houston, Texas. 

 is an assistant professor of psychiatry research at Baylor College of Medicine. ❒

The rapidly changing field of cannabinoids and their clinical implications poses a particular challenge in psychiatry.

About 50 years ago (1968) in an early edition of Resident Physician, a progenitor of 

 Herbert Berger, MD (Chairman of the Committee on Alcoholism and Narcotic Addiction, New York State Medical Society) wrote about the “Physicians’ Retreat from Management of Addictions” and blamed physician attitudes for turning over this major medical challenge to non-medical personnel and the criminal justice system. This retreat from potential patients was not just active rejection from physicians’ offices but an omission of responsibility to counter the prevalent argument that these individuals were willfully evil rather than sick.

Berger went on to discuss the 1919 interpretation of the

-that keeping an opioid dependent patient “comfortable by maintaining his customary [opioid] use was not a prescription, within the meaning of the law . . . .” As a result, physicians became targets for arrest and imprisonment for prescribing narcotics to control withdrawal symptoms in attempt to make their patients comfortable. Had any progress been made from 1919 to 1968, when Dr Berger wrote his appeal?

Interestingly, on this very same page of the article in 1968 was an advertisement from Smith, Kline, and French Laboratories stating in bold type, “To reduce pain-narcotics” followed on the next page by the statement, “To reduce narcotics-Thorazine.”

As some of us may remember, chlorpromazine was used for opioid withdrawal in the late 1960s through the 1980s (and even into the 1990s in some settings), when going cold turkey was the option. In fact, chlorpromazine was frequently given to opioid dependent arrestees during incarceration, although they did not like its effects. It was never FDA approved for this purpose. Other off-label medications also were used for reducing opioid withdrawal symptoms, including the use of clonidine for 

. However, off-label marketing was quite common at that time and continued with a vengeance for opioids such as oxycontin for chronic pain, with the subsequent problems and fines against manufacturers that bring us to modern day.

Overall, the two components of the Smith, Kline, and French Laboratories (and other pharmaceutical) advertising campaign were problematic. First, reducing pain was generalized to any pain, including benign chronic pain such as backaches, headaches, peripheral neuropathies, fibromyalgia pain, and other chronic pain conditions that do not benefit from long-term opioids. Second, reducing opioids was not easy and could not be simply treated with essentially aversive medications such as chlorpromazine, which did not target the underlying neurobiology driving opioid withdrawal symptoms. Thus, little progress with the pharmaceutical industry was evident in 1968, but plenty of future problems were starting, which the next 50 years-from 1968 to the present-began addressing.

Progress has been more evident during these more recent 50 years, moving us further away from the 1919 decisions that made it illegal to provide medical help to people with an opioid addiction. While medical progress has been slow, it has been steady. In the 1970s, because of the discovery by Vincent Dole, MD, and Marie Nyswander, MD, and the efforts of the federal government led by Jerome Jaffee, MD, the national Drug Czar, the introduction of methadone maintenance provided a wide-spread agonist treatment. Parallel work led to two important milestones: 

 as a blocker for opioids and its evolution to an injectable long-acting formulation as well as the development of 

 as a partial agonist maintenance agent. In addition, the Data2000 legislation provided more relaxed prescribing restrictions. In addition to these maintenance approaches to treatment, aids for managing the symptoms of opioid discontinuation, such as clonidine and most recently lofexidine, also became available.

We have made significant progress in moving addiction into the medical treatment area and away from the social stigma that led to widespread incarceration of those with substance use disorders. Current treatments show good efficacy for opioids and promising research is ongoing for alcohol and stimulants.

However, along with the more humane treatments for addiction, an opposing trend began from the pharmaceutical industry to increase sales of opioids for managing “insufficiently treated” chronic pain syndromes. This trend during the 1990s resulted in the lawsuits and ongoing settlements for damages that began in 2007.

We have arrived at a time for financial settlements with some of the pharmaceutical companies that derived substantial profits from what resulted in an epidemic of death and destruction as a result of opioid overuse and dependence. Based on recent court settlements of single state cases, negotiations for national settlements might reach $10 billion for each company.

In Ohio and in a recent Oklahoma case, the judge stated that one company “engaged in false and misleading marketing of both their drugs and opioids generally, and the law makes clear that such conduct is more than enough to serve as the act or omission necessary to establish the first element of Oklahoma’s public nuisance law.”

Having such massive infusions of funding into public coffers can bring great benefits to treatment of substance use disorders, damage 

, and new treatment discoveries. However, we need to look back at the Master Settlement Agreement (MSA) from the tobacco lawsuits that were settled 20 years ago in 1998.What happened with those billions of dollars? States collected an estimated $27.3 billion from the MSA and taxes in fiscal year 2019, yet today no state funds tobacco prevention at the level recommended by the 

Centers for Disease Control and Prevention

 (CDC). Overall, states spend less than 3% of MSA funds on programs that would help prevent smoking in youth and help smoking cessation. Twenty-nine states and the District of Columbia spend less than 20% of the CDC recommendation. On the other hand, Alaska and California spend more than 70% of the CDC recommended funding-$655 million annually-on prevention and cessation programs. In contrast, tobacco companies spend more than $14 to market tobacco products for every $1 the states spend to reduce tobacco use.

Because there are new challenges in reducing tobacco and nicotine use since the agreement, the MSA funds could have been better directed to detecting and addressing future threats than to the many other conditions unrelated to health care for which they were used. Among the new challenges is e-cigarette use by youths, which has skyrocketed to epidemic levels; the CDC and FDA show that from 2017 to 2018 e-cigarette use increased by 78% among high school students (to 20.8%) and by 48% among middle school students (to 4.9%).

The associated morbidity and mortality attributed to vaping with e-cigarettes has been startling and led to dramatically quick actions by Federal government standards, but with no benefit from the MSA funds. Similarly, the legalization of cannabis and its widespread smoking and vaping in many parts of the US has brought with it many health burdens in psychiatric and medical comorbidity, which have not been addressed with any portion of the MSA funds.

This lack of vision and missed opportunities associated with MSA funds should not be repeated with the accumulating opioid epidemic settlement funds. The obvious parallel for opioids with comorbid abuse of other DEA scheduled medications such as stimulants and sedatives strongly argues that these opioid settlement funds need essential investments in prevention, treatment, and research into related types of addictive substances and their delivery systems. However, such an investment is not likely to happen without substantial effort from the medical community.

To jump start these future opioid settlement funds, the federal government currently has allocated funding for the Helping to End Addiction Long-term (HEAL) initiative for the ongoing epidemic of deaths, which are now primarily from fentanyl. These HEAL funds are very welcome in the field and should provide some significant help for our patients, but these funding sources are not sustained and even their re-authorization in Congress will only carry for another year. Thus, the upcoming challenge will not be in the courts, but in the state legislatures, which are likely to get a substantial influx of financial resources for sustained periods from the opioid settlements.

These funds can help address the current opioid epidemic, but perhaps more importantly, these sustained funds need to be directed toward the rapidly growing epidemic of stimulants, particularly methamphetamine. While the fatalities associated with this opioid epidemic have indeed shifted to an illicit market of heroin and fentanyl and away from the original challenges with marketed commercial opioids, fentanyl is not only mixed with opioids, it is also being mixed with stimulants and causing increased mortality among drug users.

 are also fueled by pharmaceutical companies who market stimulants for adults and children with attention-deficit/hyperativity disorder; however, many adults are getting stimulants for such off-label uses as depression, anxiety, and improved concentration. College campuses are awash in illicit stimulant use, and many young adults are becoming addicted to stimulants. Moreover, there is now the added risk of illicit fentanyl adulteration and overdose.

The financial resources that are clearly on their way to states and communities from both pharmaceutical company settlements and the more immediate federal HEAL grants need appropriate planning for wise spending-not wasting these resources by missing the mark for which they were intended.

So, have we made progress since that article was published in 1968 or are we on a two-steps forward, one backward pattern? Let us hope a future psychiatrist will be able to write a more positive article.

 is Jay H. Waggoner Endowed Chair, Co-Founder, Institute for Clinical and Translational Research, and Professor of Psychiatry, Neuroscience, Pharmacology, and Immunology, Baylor College of Medicine, Houston, TX.

1. Campaign for Tobacco-Free Kids. A State-by-State Look at the 1998 Tobacco Settlement 21 Years Later. January 16, 2020.

How much progress has been made in the area of substance use disorders in the last 40 years?

Are We Making Any Progress in Treatment and Attitudes?

Judgements and settlements are starting in Oklahoma against various pharmaceutical companies for their alleged roles in that state’s 

crisis. During these judgements and negotiations with three major companies, the financial liability potentially ranged from a judgement for more than $500 million in this single state case to negotiations that might reach $10 billion for each company to resolve national claims. In this most recent Oklahoma case, the judge stated that one company “engaged in false and misleading marketing of both their drugs and opioids generally, and the law makes clear that such conduct is more than enough to serve as the act or omission necessary to establish the first element of Oklahoma’s public nuisance law.”

Several aspects of this ruling seem remarkable and perhaps contradictory. From a conventional understanding of a “public nuisance,” this bland-sounding civil offense seems relatively minor and hardly the basis for a significant financial judgement. Police officers may issue fines for a public nuisance offense, which is a ticket with a payable fine that ranges from $100 to $300. From an international perspective, the Indian Penal Code states that a public nuisance “. . . shall be punished with a fine, which may extend to two hundred rupees,” which is equivalent to about $3. Is the severity of the alleged pharmaceutical manufacture’s public nuisance offense consistent with the magnitude of the financial liability in this judgement?

Compared with the tobacco smoking settlement amounts for hundreds of billions of dollars or to the Wall Street analysts’ expectation of a fine up to $5 billion for this case in Oklahoma, this $500 million seems a relatively modest amount to pay. The importance of this initial landmark case is of course significant; however, we need to recognize that nationally more than 2000 additional court cases are still pending. Moreover, the recent Purdue offer to settle its 2000 pending opioid related lawsuits for $10 to $12 billion needs to be recognized.

Since most major pharmaceutical companies and wholesale distributors are defendants in these nationally pervasive cases, how large could the ultimate pool of funds be? If each of these 20 to 30 companies was required to pay even $500 million over 2000 lawsuits the national settlement would be about $10 billion each. The $10 billion from a single company would lead to about $6 million for each of the municipal plaintiffs, which, when multiplied by the 20 to 30 companies with pending lawsuits, would result in hundreds of billions of dollars to distribute.

What is the implication of having hundreds of billions of dollars available for addiction disorders, mental health, and other health care services? Would these be the only beneficiaries of these funds? In 2017, the White House Council of Economic Advisors estimated the national health care costs related to the opioid epidemic to be about $500 billion, but that estimate is of money already spent and does not offer a framework for spending new funds from a settlement with the pharmaceutical companies.

Furthermore, by 2017 much of the fatal and catastrophic outcomes associated with opioids were attributable to heroin and illicit fentanyl, not pharmaceutic company sources. Thus, what portion of any final settlement would health care components deserve to provide care for the estimated 11 million current and potentially future substance use disorder patients? We might learn something from the tobacco company financial settlements and their distribution across the US, when the period of being a public nuisance lasted considerably longer and had an impact on a substantially larger proportion of the population.

A look back on the benefits for addictions prevention and treatment and for health care broadly is not encouraging on this 20th anniversary of the Master Settlement Agreement (MSA), which is an accord reached in November 1998 between the state Attorneys General of 46 states, five US territories, the District of Columbia, and the five largest cigarette manufacturers in America. This MSA settlement required the tobacco industry to pay the settling states billions of dollars annually forever. Specifically, the MSA also had the original participating manufacturers agree to pay a minimum of $206 billion over the first 25 years of the agreement. Over the years, the states have collected tremendous amounts of revenue related to the MSA, but are spending little of it on tobacco prevention and cessation programs.

States collected an estimated $27.3 billion from the MSA and taxes in fiscal year 2019, yet today no state funds tobacco prevention at the level recommended by the Centers for Disease Control and Prevention (CDC). Overall, states spend less than 3% of MSA funds on programs to prevent kids from smoking and help smokers quit. Twenty-nine states and the District of Columbia spend less than 20% of the 

Alaska and California spend more than 70% of the CDC recommended funding-$655 million annually on prevention and cessation programs. Tobacco companies, on the other hand, spend more than $14 to market tobacco products for every $1 the states spend to reduce tobacco use.

Despite overall progress in reducing smoking rates to 14%, smoking rates are highest among people with lower income and less education, American Indians/Alaska Natives, LGBT Americans, those who are uninsured or on Medicaid, and those with mental illness. These differences are in part due to the misallocation of these MSA funds to many other conditions unrelated to health care, prevention, and biomedical research.

New challenges have also evolved in the spread of nicotine abuse and dependence among youth. Youth 

 has skyrocketed to epidemic levels; the CDC and FDA show that from 2017 to 2018 e-cigarette use increased by 78% among high school students (to 20.8%) and by 48% among middle school students (to 4.9%). The obvious parallel for opioids with the many other DEA scheduled medications such as stimulants and sedatives strongly argues that investments of these settlement funds in prevention, treatment, and research in related types of addictive substances and their delivery systems is essential. However, how likely is that to happen based on our experience with the MSA for tobacco and nicotine?

The funds are available to put into health care, particularly for the youth of America, but our state leaders are not funding these programs at levels recommended by the CDC. Thus, the upcoming challenge will not be in the courts, but in the state legislatures, which are likely to get a substantial influx of financial resources to address the current epidemic with opioids. The fatalities associated with this epidemic have indeed shifted to an illicit market of heroin and fentanyl and away from the original challenges with marketed commercial opioids. Nevertheless, financial resources are clearly on their way to states and communities, and we need appropriate planning for wisely spending-not wasting these resources by missing the mark for which they were intended.

Dr Kosten is Jay H. Waggoner Endowed Chair, Co-Founder, Institute for Clinical and Translational Research, and Professor of Psychiatry, Neuroscience, Pharmacology, and Immunology, Baylor College of Medicine, Houston, TX.

1. Campaign for Tobacco Free Kids. A State-by-State Look at the 1998 Tobacco Settlement 20 Years Later; 2018. 

https://www.tobaccofreekids.org/what-we-do/us/statereport

Judgements and settlements are starting in Oklahoma against various pharmaceutical companies for their alleged roles in that state’s opioid crisis. Who would be the beneficiaries of these funds?

The Opioid Epidemic Settlements: Who Will Benefit?

Patients on opioids for chronic pain management develop common complications that respond best to discontinuation and consideration of alternative pharmacotherapies, often in combination with behavioral interventions. A presentation at the October 2019 Psych Congress in San Diego covered these chronic opioid complications in detail. This overview addresses two medications for analgesia of chronic benign pain, both of which have substance abuse risks themselves-cannabinoids and 

are associated with complications in terms of their use, potential for abuse, and administration. Without concurrent opioids, cannabinoids’ efficacy as an analgesic is poor; and 10% of people who use tetrahydrocannabinol (THC) become addicted to it.

In addition, the cannabinoids, particularly cannabidiol (CBD), can potentiate the efficacy to, and reduce tolerance to, opioids. This brief overview focuses on CBD, because data and legal regulation have been rapidly progressing for its potential role in chronic pain management both within psychiatric and primary care settings. Furthermore, all 50 states have laws legalizing CBD with varying degrees of restrictions, and many people obtain CBD online without a medical cannabis license or physician prescription.

Although we do not know the most effective therapeutic dose of CBD for pain, some preliminary estimates are available, such as the 5mg/kg twice-daily dose of Epidiolex for treating two rare seizure disorders.

 Moreover, we can compare analgesic effects using the number of patients needed to treat (NNT) for a clinically significant therapeutic effect. Tricyclic antidepressants and opioids have the lowest NNT for treating neuropathic pain (2.6 and 2.1, respectively).

 This NNT means that for every single patient showing a therapeutic response to each of these agents, we need to treat 2.6 patients and 2.1 patients for tricyclics and opioids, respectively. Perhaps more simply, one of every two patients treated with opioids will have satisfactory analgesia from chronic neuropathic pain. In comparison, an oral CBD spray was found to have an NNT of 5.0, which is comparable to many routine agents used in treating neuropathic pain, including SSRIs (NNT=5.0) and gabapentin (NNT=6.4).

It is also important to look at the negative aspects of treatment. A meta-analysis of 18 double-blind, randomized controlled trials on CBD efficacy analyzed the harms associated with CBD. They found that the number needed to harm (NNH) with CBD, which ideally would be high, was instead relatively low. For CBD, the NNH ranged from 5 to 8 patients, while other analgesics have NNH values above 20.

Specific adverse events contributing to the poor value for NNH included impaired motor function (NNH=5), altered perception (NNH=7), and altered cognitive function (NNH=8). Thus, assessing the efficacy of CBD must be balanced against the potential for harm in the management of neuropathic pain.

The CBD oral solution Epidiolex is available in the US for management of refractory epilepsy, but it has been used off label for chronic pain conditions.

 GW pharmaceuticals also produce nabiximols, which is a marijuana extract currently approved in the UK to treat neuropathic pain, pain due to spasticity, overactive bladder, and other symptoms associated with multiple sclerosis. GW Pharmaceuticals is currently planning Phase 3 trials for nabiximols in the US.

 Thus, these medications are likely to become available in FDA-approved formulations at doses that have potential analgesic efficacy in the not too distant future.

The role of ketamine for chronic pain is more complex, including the setting for delivery. However, ketamine use for chronic pain could be adopted within the specialized psychiatry settings that the new REMS (Risk Evaluation and Mitigation Strategies) programs are mandating for esketamine to treat depression.

Ketamine might best be considered among the antidepressants that have consistently shown efficacy for chronic pain in conditions such as peripheral neuropathy, diabetic neuropathy, phantom limb pain, and patients with depression and pain.

 The relative efficacy of antidepressants based on NNT follows the efficacy of opioids, which has an NNT of 2.1, as previously noted. In comparison, the NNT for similar opioid alternatives are as follows: 3.6 for tricyclic antidepressants; 6.4 for serotonin- norepinephrine reuptake blockers; 7.2 for gabapentin; and 7.7 for pregabalin. However, the onset of full efficacy for opioids is rapid (and usually only a few minutes after oral ingestion), while these other medications typically take six to eight weeks for full efficacy as analgesics.

In contrast to the slow onset for these antidepressant and related agents, ketamine for chronic pain has shown surprisingly quick and long-lasting results. Ketamine has obvious acute analgesic efficacy, and sustained infusions of ketamine over one to 100 hours have produced sustained analgesia for months after these single treatments.

 Specifically, one study found substantially reduced chronic neuropathic pain after 30 minutes of ketamine infusion at 0.5 mg/kg, but this relief only lasted several hours in some patients. A second set of studies using 100-hour infusions of ketamine at 20 to 30 mg/hour or 4-hour daily infusions for 10 days relieved pain for three months, but relief started declining by four to six weeks after the acute treatments. Overall, these ketamine studies showed large effect sizes in the first week following treatment (1.2; 

<.001), but by week four, the effect sizes dropped to 0.4 (although they remained statistically significant at 

=.04). Unfortunately, these reports are five to 10 years old, and there are not more recent reports. Similarly, there are no studies using the newly available intranasal formulation of esketamine, which would make the administration easier than the previous intravenous studies.

These ketamine studies have some important caveats:

• There was no improvement in functionality with analgesia from ketamine.

• Cognition and memory impairment may be persistent with longer duration or more frequent administration; and no long-term data exist.

• Ketamine has negative inotropic effects on the heart and can produce elevated liver functions with repeated dosing.

• Less serious side effects include drowsiness and dizziness during repeated treatment (about one-quarter of patients reported these symptoms).

• Dissociation and abuse are potential psychiatric complications from even a single administration of ketamine.

Chronic pain continues to be a hot button issue, and psychiatrists need to be aware of non-opioid options, especially for their patients with substance use histories. Both ketamine and CBD are on the horizon as new treatments for chronic pain. Since both have risks for inducing substance use disorders, their use needs to be considered cautiously.

Dr Kosten is Professor at the Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine and Staff Psychiatrist at Michael E. DeBakey VA Medical Center, Houston.

. Diagnostic and Statistical Manual of Mental Disorders

). Washington, DC: American Psychiatric Association Press; 2013.

2. National Academies of Sciences, Engineering, and Medicine. 

The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research

http://nationalacademies.org/hmd/reports/2017/health-effects-of-cannabis-and-cannabinoids.aspx

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https://www.goodrx.com/blog/what-is-esketamine-spravato-nearing-fda-approval.

4. Wilkinson ST, Howard DH, Busch SH. Psychiatric practice patterns and barriers to the adoption of esketamine. 

.  August 2, 2019. doi:10.1001/jama.2019.10728

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https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf

6. Urits I, Borchart M, Hasegawa M et al. An update of current cannabis-based pharmaceuticals in pain medicine. 

7. MartÃ­n-SÃ¡nchez E, Furukawa TA, et al. Systematic Review and Meta-analysis of Cannabis Treatment for Chronic Pain. 

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14. Perucca E. Cannabinoids in the treatment of epilepsy: hard evidence at last? 

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19. Kalsi SS Wood DM, Dargan PI. The epidemiology and patterns of acute and chronic toxicity associated with recreational ketamine use. 

This overview addresses two medications for analgesia of chronic benign pain, both of which have substance abuse risks themselves.