IV NAD Significantly Improves Withdrawal Symptoms Associated with Chronic Opioid Exposure

Intravenous Administration of Nicotinamide Adenine Dinucleotide Significantly Improves Withdrawal Symptoms Associated with Chronic Opioid Exposure

Susan Broom Gibson, PhD
November 20, 2020

Presentation Summary/Objectives

Discuss the neuro-mechanisms and behaviors associated with the positively and negatively reinforcing effects of chronic opioid exposure and emphasize the importance of developing treatment protocols that provide therapeutic benefits while minimizing abuse liability.

Evaluate results from retrospective studies utilizing IV NAD+ administration protocols in treating symptoms associated with acute withdrawal.
Present data from ongoing studies evaluating long term outcomes of IV NAD+ in the treatment of opioid use disorders.
Dopamine Reward Pathway

Acute Exposure to substances such as Alcohol, Opioids, Psychostimulants and Benzodiazepines cause increased release of DA in the NA; Amount of dopamine released determines level of reward (i.e., positively reinforcing effects).
Also, small increases in stress-induced DA in NACC are a sign of coping with stressors (i.e., negatively reinforcing effects).

Chronic Use Disrupts The Mesolimbic Dopamine Pathway

Environmental cues trigger cravings and the behaviors necessary to satisfy those cravings (i.e., conditioned responses)

Chronic substance use can cause functional changes in the mesolimbic
Dopamine pathway resulting in functional changes in behavior
(i.e, operant conditioning) that are resistant to extinction.

Development of Classically Conditioned and Operant Conditioned Behaviors During Acute and Chronic Drug Exposure

Classical Conditioning = Behaviors develop due to associative S-R relationships (“triggers”, compensatory responses, cravings, anticipatory behaviors)

Positive Reinforcement = Occurrence of behavior increases due to addition of a good consequence (intoxication, reward, euphoria)

Negative Reinforcement = Occurrence of the behavior increases due to removal of a bad consequence (pain, anxiety, cravings)

Connecting brain structure to function in the Addiction Cycle is key in the establishment of SUD’s as BRAIN DISEASES

Volkow, N. D., Koob, G. F., & McLellan, A. T. (2016). Neurobiologic advances from the brain disease model of addiction. The New England Journal of Medicine, 374(4), 363–371. https://doi-org.wmcarey.idm.oclc.org/10.1056/NEJMra1511480

Long Term Consequences

Tolerance- reduced effects due to repeated administration of the same dose.  (Can happen at the behavioral and cellular level)

Withdrawal- symptoms are both psychological (i.e., cravings) and physiological (i.e., opioid withdrawal syndrome).

These symptoms further contribute to the maintenance of maladaptive behaviors associated with substance use disorders due to negatively reinforcing properties

Traditional Treatment (Medical Assistance Therapy)

Naltrexone and Naloxone are opioid antagonists and produce immediate reversal of opiate effects.  Most commonly administered in opioid overdose.

Methadone is a synthetic opioid that blocks the effects of heroin and other opioids, eliminates withdrawal symptoms, and relieves drug craving. Methadone reduces severity of opioid withdrawal and allows patients to “taper off”.

Buprenorphine is a partial mu-opioid receptor agonist and kappa-opioid receptor antagonist.  Approved in 2002, it has a longer half-life and less severe withdrawal syndrome.  Results mixed regarding effectiveness compared to Methadone.

Limitations

These clinical conditions are perceived as complex brain diseases that are chronic and relapsing in nature; current approaches are lacking in evidence-based approaches that address these issues.

Despite their success at acute detox, these traditional approaches (combined with the associated stigma and treatment as a criminal justice issue) lack support in addressing safety concerns and measurable success in long term positive outcomes (i.e., participation in follow-up, reduced relapse rates)

MAT fails to adequately address how clinicians can treat patients without creating problems long term (i.e, treating a drug with a drug).

Clinical Guidelines for Withdrawal Management and Treatment of Drug Dependence in Closed Settings. Geneva: World Health Organization; 2009. 4, Withdrawal Management. Available from: https://www.ncbi.nlm.nih.gov/books/NBK310652/

Volkow, N. D., Poznyak, V., Saxena, S., Gerra, G., UNODC-WHO Informal International Scientific Network (2017). Drug use disorders: impact of a public health rather than a criminal justice approach. World psychiatry : official journal of the World Psychiatric Association (WPA), 16(2), 213-214.

Volkow, N. D., Koob, G. F., & McLellan, A. T. (2016). Neurobiologic advances from the brain disease model of addiction. The New England Journal of Medicine, 374(4), 363–371. https://doi-org.wmcarey.idm.oclc.org/10.1056/NEJMra1511480

Proposed Solution: BR+NAD®

Optimal therapies will maximize therapeutic effects while minimizing abuse liability

In other words, these approaches will safely help the brain restore healthy cell function and maintain sobriety over the long term by alleviating cravings and reducing relapse episodes.

It is also of importance that combinations of approaches particularly focused on after care support will lead to higher success in the long term

Evaluate results from retrospective studies utilizing IV BR+NAD® administration protocols in treating symptoms associated with acute withdrawal.

Mestayer, P.N. & With Goodman, L. (2019). Addiction: The Dark Night of the Soul/ NAD+: The Light of Hope. Balboa Press.

Pilot Study 1: The Effects of IV NAD+ on Opioid and Alcohol Withdrawal

Retrospective analysis performed to examine the anti-craving properties of NAD+ in a group of 60 patients.

The patients were adult males and females with addictions to primarily opiates and alcohol.

The treatment comprised of IV infusions of NAD+ as well as vitamins, oral amino acids and variable PRN medications (BR+NAD®) for an average of 10 consecutive days ranging from 5 to 10 hours daily.

Self-reported craving ratings (1-10 Scale) were collected on Day 1 (before starting treatment), Day 5, and on Day 10 (after completion of treatment; see Figure 2).

Intravenous Administration of Nicotinamide Adenine Dinucleotide Significantly Reduces Self Report Craving Ratings Associated with Opiate and Alcohol Withdrawal (Broom, Mestayer, Stuller, Cook, Carson, Simone, Norris, Hotard. Society For Neuroscience Poster 2014).

BR+NAD® is an effective detox treatment for alcohol and opioid substance use disorders as evidenced by a significant reduction in craving ratings (SFN 2014).

The Retrospective Study Phase II (Protocol updated in 2017)

Expanded population numbers for both groups; still using pre-existing chart information from self report and nurses’ notes as well as standardized assessments.

Includes additional Short Term Outcome measures (STO’s) in response to IV BR+NAD®.  Additional data obtained from SWC population where available included:

  • Demographic information (age and sex) and completion rates (completed minimum of 8 days IV BR+NAD®).
  • Patient Reported Cravings, Anxiety, Depression, Pain, Sleep (also reported on nurses’ notes).
  • First 5 days of COWS/ CIWA scores.
  • Measures of plasma NAD+, NAD/NADH ratios, Inflammatory markers

Broom, S.L., Mestayer, R., Simone, K., Summers, S. The Effects of Intravenous Nicotinamide Adenine Dinucleotide on Withdrawal Symptoms Associated with Opiate and Alcohol Addiction: A Retrospective Analysis (WCU IRB exempted review November 2017; manuscript in prep).

Demographics and Descriptive Data for the Opioid Group

The Opioid Group averaged 36 (+/-1.95) years of age comprised of 81.08% Males and 13.51% Females (2 unspecified).

The pattern of withdrawal symptoms noted on the COWS assessment form in comparison to the patient reported cravings rating support that patients are experiencing withdrawal defined as LOW severity according to COWS and MODERATE-SEVERE on cravings ratings. 

Three/eighteen patients had a COWS score reported for DAY 6 (scores 2, 5, 9) and one patient had scores reported for days 6 through 10 (scores 9, 7, 9, 3, 4). 

Safety Measures Reported in Patients receiving IV BR+NAD® (2008-2017)

No adverse events were reported from IV BR+NAD® treatment over the first 3 days.

Initial Observations: The nurses’ notes page for patient rated symptoms (scaled 0-10) of cravings, anxiety, depression, irritability and pain were limited; however anxiety, depression, irritability and pain averaged less than 3 (anxiety Day 1 was 3.4) across the 10 day IV NAD+ treatment period, consistent with the COWS scores indicating a less severe withdrawal.

Typical withdrawal symptoms reported in the Opioid group included changes in sleep (insomnia) and appetite (nausea, poor), stomach and muscle cramps, and G.I. distress (diarrhea).  It should be noted that these symptoms appeared to be dropping off by DAY 7.

IV BR+NAD® Significantly Reduces COWS Scores by Day 5 of Treatment Protocol

Average COWS scores (+ SEM) as a function of treatment day.  Average scores slightly increased on DAY 2 then significantly decreased by the fifth day of IV BR+NAD® infusion. In summary, the COWS scores for this group indicate that these patients were in the MILD range of withdrawal across all 5 days of IV NAD+ treatment.  Single factor ANOVA revealed a significant decrease in COWS scores by DAY 5 (p = 0.044).  Paired t tests revealed a significant decrease in COWS scores between DAY 1 vs DAY 5 (p = 0.006 one tail; p = 0.011 two tail).

Changes in Circulating Oxidative Stress & Pro-Inflammatory Markers and Correlations with Withdrawal Symptoms in Opioid Patients Following IV NAD+

Sharp, T.E., Polhemus, D.J., Bennet, J., Broom, S.L., Mestayer, P.N., Lefer, D.J., Mestayer, R.F. (2017). Improved Withdrawal Symptoms and Reduced Oxidative Stress and Inflammation Following Intravenous Nicotinamide Adenine Dinucleotide Therapy in Opiate and Alcohol Abuse Patients. Research Funded by NAD Research, Inc.

Present data from studies evaluating long term outcomes of IV BR+NAD® in the treatment of opioid use disorders.

Assessment of Long Term Outcomes

Original form used in SFN 2014 Study

Chart records for the 2014 follow-up date indicated that 45% of the original sample (27/60) participated in and completed long term follow-up phone surveys.  This included 13 opioid patients and 14 alcohol patients.

61.5% (8/13) Opioid patients received at least 1 booster between original rotation date and follow-up call


BR+NAD
® effectively reduced severity of drug cravings over a 12-20 month follow up period (SFN 2014). 

Time of Follow-up Call

 

BR+NAD® effectively reduced the number of relapse episodes over a 12-20 month follow up period (SFN 2014). 

Time of Follow-up Call

1 Opioid patient reported 4 episodes in a 15 month period

Pilot project (Summer 2020) used an updated form and called/emailed patients from the original studies carried out between 2008-2014

Updated Follow-up Survey (2020)

  1. Have you participated in any aftercare programs since your discharge from Springfield Wellness Center?

If answer is YES:  What kind of programs have you participated in? 

  1. Have you had any slips in usage since your treatment (0-3 Rating)?

If answer is YES:  With a MILD (1 rating); a MODERATE (2-3 rating) and SEVERE (3 or > rating)

  1. Are You Participating in 12 Step Programs (y/n)? If yes, how often? 
  1. Did you return for any IV boosters?

If answer is YES:  How many?  Improvement Rating (1 no improvement to 5 most improvement) 

  1. Are you taking NAD melts, nasal spray, patches?

If answer is YES:  What dose/frequency?  What happened when you stopped? 

  1. On a scale of 1 to 5, with 1 being minimal and 4 being severe, how would you rate your cravings today? 

On a scale of 1 to 5, with 1 being not helpful and 5 being very helpful, how would rate the usefulness of the IV therapy?

*Charts included Opioid patients treated from 2008-2017 (some of these patients were from the 2014 study)

Results

*2 of the 6 respondents to date have completed survey by phone

*Summary of results:  Overall positive (no slips, no cravings)

Conclusions

BR+NAD® is a safe and effective detox treatment for alcohol and opioid use disorders as evidenced by a significant  reduction in craving ratings.

BR+NAD® showed potential as a long-term therapy in maintaining sobriety through minimizing drug cravings and preventing relapse.

Follow-up research indicates that IV NAD+ is comparable to traditional standard of care settings as indicated by participation in follow-up surveys, cravings ratings and relapse episodes; however continued research should remain focused on improvements in follow-up communication, participation and measurement of long term outcomes.

Acknowledgments

BR+MD Consultants, LLC-Richard Mestayer, MD

Springfield Wellness Center-Paula Norris-Mestayer, MEd, LPC

SWC Staff- James Bennett, Karen Simone, Sherry Summers, Dr. Tyson Olds, Paula Hotard, Michelle Starkey MS, PLPC, NCC, LAC

NAD Research, Inc. –Science Advisory Board Members

LSU Health Sciences Center, New Orleans, LA- Dr. Lefer, Dr. Sharp, Dr. Polhemus

Archway Apothecary, Covington, LA

William Carey University Professional Development Grant Committee

William Carey University Institutional Review Board