Lynn R. Webster, M.D.

The following are selected publications by area of research.

Risk assessment for opioid use disorder.

Risk assessment for potential misuse, abuse, and addiction (opioid use disorder) was not a common practice when opioids were first routinely prescribed for chronic non-cancer pain in the 1990s. Although, in the nineties, it was known that people who were prescribed an opioid could become addicted to an opioid, it was less clear who was at greatest risk of harm. The lack of science and understanding about which patients were most vulnerable to adverse outcomes from opioid exposure has been the basis of much of my research.

• Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid risk tool. Pain Medicine 2005;6(6):432-42.
• Webster LR, Dove B. Avoiding Opioid Abuse While Managing Pain: A Guideline for Practitioners. 1st Edition. North Branch, MN: Sunrise Press; 2007.
• Webster LR. Screening for the risk of substance abuse in pain management. In: Smith HS, Passik SD, eds. Pain and Chemical Dependency. 1st Edition. New York, NY: Oxford University Press; 2008:Chapter 47;395-405.
• Webster LR. The Prescription Drug Abuse Epidemic and Emerging Prescribing Guidelines. In Benzon HT, Raja S, Liu SS, Fishman SM, Cohen SP, eds. Essentials of Pain Medicine. 4th edition. Philadelphia: Saunders Elsevier, 2018:389-394.
• Webster L. Risk Mitigation Strategies. In: Staats P, Silverman S, eds. Controlled Substance Management in Chronic Pain. First Edition. Switzerland: Springer 2016; 163-180.
• Webster LR, Gitlow S. Addictive disorders and pain. In: Deer TD, Leong MS, Buvanendran A, Gordin V, Kim PS, Panchal SJ, Ray AL, eds. Comprehensive treatment of chronic pain by medical, interventional, and integrative approaches: The American Academy of Pain Medicine textbook on patient management. 1st Edition. New York, NY: Springer; 2013; Chapter 73;787-
• Webster LR. Screening for the risk of substance abuse in pain management. In: Smith HS, Passik SD, eds. Pain and Chemical Dependency. 1st Edition. New York, NY: Oxford University Press; 2008:Chapter 47;395-405.
• Webster L. Risk Mitigation Strategies. In: Staats P, Silverman S, eds. Controlled Substance Management in Chronic Pain. First Edition. Switzerland: Springer 2016; 163-180.

Clinical human abuse potential research

Assessing the abuse potential of drugs is essential for all CNS drugs as part of their safety evaluation. The clinical studies help characterize the drug’s potential to be used for non medical purposes, if approved. The human abuse potential studies help the FDA and DEA determine the drug’s scheduling and labeling. Abuse potential studies have been critical for determining labeling for abuse deterrent formulations. The following are a few citations that reflect my work in the area.

• Webster LR, Brewer R, Wang C, Sekora D, Johnson FK, Morris D, Stauffer J. Long-term safety and efficacy of morphine sulfate and naltrexone hydrochloride extended release capsules, a novel formulation containing morphine and sequestered naltrexone, in patients with chronic, moderate to severe pain. Journal of Pain and Symptom Management. November 2010;40(5):734-746.
• Webster LR, Johnson FK, Stauffer J, Setnik B, Ciric S. Impact of intravenous naltrexone on intravenous morphine-induced high, drug liking, and euphoric effects in experienced, nondependent male opioid users. Drugs in R&D. 2011;11(3):259-275.
• Webster LR, Bath B, Medve RA, Marmon T, Stoddard GJ. Randomized, double-blind, placebo-controlled study of the abuse liability of different formulations of oral oxycodone. Pain Medicine. 2012;13(6):790-801.
• Webster LR, Rolleri RL, Pixton GC, Sommerville KW. Randomized, double-blind, placebo controlled and active-controlled study to assess the relative abuse potential of oxycodone HCI niacin tablets compared to oxycodone alone in nondependent recreational opioid users. Substance Abuse & Rehabilitation. 2012;3(1):101-13.
• Soergel DG, Subach RA, Burnham N, Lark MW, James IE, Sadler BM, Skobieranda F, Violin JD, Webster LR. Biased agonism of the mu opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: a randomized, double-blind, placebo controlled crossover study in healthy volunteers. PAIN. 2014;155(9):1829-35.
• Devarakonda K, Kostenbader K, Zheng Y, Mongtomery JB, Barrett T, Young JL, Webster LR. Human abuse potential of immediate-release/extended-release versus immediate-release hydrocodone bitartrate/acetaminophen: a randomized controlled trial in recreational users of prescription opioids. Postgraduate Medicine. 2015;127(1):13-21.
• Webster L, Kopecky E, Smith M, Fleming A. A Randomized, Double-blind, Double-Dummy Study to Evaluate the Intranasal Human Abuse Potential and Pharmacokinetics of Xtampza ER™, a Novel Extended-Release Abuse-Deterrent Formulation of Oxycodone. Pain Medicine. 2015; 0: 1-19; doi: 10.1093/pm/pnv020.
• Webster L, Pantaleon C, Shah S, DiFalco R, Iverson M, Smith M, Kinzler E, Aigner S. A randomized, double-blind, double-dummy, placebo-controlled, intranasal drug liking study on a novel abuse-deterrent formulation of morphine ─ Morphine ARER. Pain Medicine (2017) 18 (7): 1303-1313.
• Webster L, Stauffer J, Spencer R, Menzaghi F, Abrouk N, Lewis M, Chalmers D. Subjective and Objective Evidence of Low Abuse Potential of the Peripherally-Acting Kappa Opioid CR845, Compared with Pentazocine. Drug and Alcohol Dependence. 2015; 156: e211. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.570
• Webster L, Heningfield J, Buchhalter A, Siddhanti S, Lu L, Odinecs A, Eldon M. Human Abuse Potential of the New Opioid Analgesic Molecule NKTR-181 Compared to Oxycodone. Pain Medicine, 2017 Mar 10. doi: 10.1093/pm/pnw344.
• Webster L, Viscusi E, Brown C, Dayno J. Human Abuse Potential Studies of Abuse-Deterrent Opioids: Lessons from Oral and Intranasal Studies with Morphine Abuse-Deterrent, Extended Release, Injection-Molded Tablets. Current Medical Research and Opinion, Vol 34(2018) 893-901. DOI: 10.1080/03007995.2018.1433144.

Studied risks of respiratory depression with clinical doses of analgesics.

Most overdose deaths are due to a combination of medications causing respiratory depression. I was one of the first investigators to show an association between opioids and sleep disorder breathing. Extremes of sleep disordered breathing can cause respiratory depression and death. I have proposed and published a methodology to evaluate the effect of drugs in development on respiratory drive. The sample of citations below show the evolution of my clinical research contribution to understanding the doses and types of drugs that have caused respiratory depression and have contributed to overdoses.

• Webster LR. Methadone side effects: constipation, respiratory depression, sedation, sleep-disordered breathing, and the endocrine system. In: Cruciani RA, Knotkova H, eds. Handbook of methadone prescribing and buprenorphine therapy. 1st Edition. New York, NY: Springer 2013; Chapter 4; 39-49.
• Webster LR, Choi Y, Desai H, Grant BJB. Sleep-disordered breathing and chronic opioid therapy. Pain Medicine. 2008;9(4):425-32.
• Mogri M, Desai H, Webster L, Grand BJB, Mador MJ. Hypoxemia in patients on chronic opioid therapy with and without sleep apnea. Sleep & Breathing. 2009;13:49-57.
• Webster LR. Considering the risks of benzodiazepines and opioids together. Pain Medicine. 2010;11(6):801-2.
• Cheatle M, Webster L. Opioid Therapy and Sleep Disorders: Risks and Mitigation Strategies. Pain Medicine. 2015 Oct; 16(0 1): S22–S26.
• Webster, L, Rauck, Richard L. Atypical opioids and their effect on respiratory drive, Journal of Opioid Management, Vol 17, No 7,
• Webster LR, Hansen E, Stoddard G, Rynders A, Ostler D, Lennon H. Ventilatory Response to Hypercapnia as Experimental Model to Study Effects of Oxycodone on Respiratory Depression, Current Reviews in Clinical and Experimental Pharmacology, 2022.
• Webster L, Cater J, Smith, T. Pharmacokinetics of Buprenorphine Buccal Film and Orally-administered Oxycodone in a Respiratory Study: An Analysis of Secondary Outcomes from a Randomized Controlled Trial. Pain Therapy, May 7, 2022.

Pharmacogenetics of opioid addiction and analgesics.

Biology describes how humans are the same while genetics describes how we are different. Vulnerability to an opioid addiction is estimated to be 50-60% genetic. Pain experience is also affected by an individual’s genotype. Although a relatively new area of clinical medicine, understanding how the human genome affects the response to pain and drugs may help provide more effective and safer therapies for pain and addiction. Below are a few examples of my emerging work in this rapidly evolving area.

• Webster LR. Pharmacogenetics of pain: the future of personalized medicine. In: Moore R.J., ed. Handbook of Pain and Palliative Care: Biobehavioral Approaches for the Life Course. Springer Science+Business Media, LLC; 2012; Chapter 26: 431-8.
• Webster L, Belfer I. Pharmacogenetics and Personalized Medicine in Pain Management. Clinics in Laboratory Medicine 36 (2016), pp. 493-506.
• Webster LR. (2018) Pharmacogenetics of pain: the future of personalized medicine. In: Moore RJ (ed) Handbook of pain and palliative care. Springer: Cham.
• Visvikis-siest S, Gorenjak V, Stathopoulou M, Petrelis A, Weryha G, Masson C, Hiegel B, Kumar S, Barouki R, Boerwinkle E, Dagher G, Deloukas P, Innocenti F, Lamont J, Marschler M, Meyer H, Meyer U, Nofziger C, Paulmichl M, Vacher C, Webster L. The 9th Santorini Conference: Systems Medicine, Personalized Health and Therapy. “The Odyssey from Hope to Practice”, Santorini, Greece, 30 September–3 October 2018. Journal of Personalized Medicine,2018, 8(43), 1-12. doi:10.3390/jpm8040043.

Studies on the safety and efficacy of analgesics that could replace conventional opioids with safer analgesics.

There is a huge unmet need for safer and more effective analgesics. The population of people with pain is growing because of an aging population, increased survival from cancer, and morbidity of post procedural pain. This has increased the need for alternatives to opioids that will improve the quality of life and limit disability for people in pain.

The following are a few publications that cited my efforts to help find safer and more effective devices and medical therapies for pain and addiction. Finding alternatives to opioids is one way to decrease the exposure to opioids. Telehealth is emerging as a potential mechanism to delivery digital medicine and to monitor effects of therapeutic modalities.

• Rauck R, Coffey RJ, Schultz DM, Wallace MS, Webster LR, McCarville SE, Grigsby EJ, Page LM. Intrathecal gabapentin to treat chronic intractable non-cancer pain. Anesthesiology. 2013;119(3):675-86.
• Quiding H, Jonzon B, Svensson O, Webster L, Reimfelt A, Karin A, Karlsten R, Segerdahl M. TRPV1 antagonistic analgesic effect: a study of AZD1386 in pain following third molar extraction. PAIN. 2013;154(6):808-12.
• Webster LR, Richards P, Stern W, Kelen R. A double-blind, placebo-controlled study of dual opioid treatment with the combination of morphine plus oxycodone in patients with acute postoperative pain. Journal of Opioid Management. 2010;6(5):329-40.
• Kalliomaki J, Segerdahl M, Webster L, Reimfelt A, Huizar K, Annas P, Karlsten R, Quiding H. Evaluation of the analgesic efficacy of AZD1940, a novel cannabinoid agonist, on postoperative pain after lower third molar surgical removal. Scandinavian Journal of Pain. 2013;4(1):17-22.
• Zebala J, Searle S, Webster LR, Johnson M, Schuler A, Maeda D, Kahn S. Desmetramadol has the Safety and Analgesic Profile of Tramadol Without Its Metabolic Liabilities: Consecutive Randomized, Double-Blind, Placebo- and Active ComparatorControlled Trials. The Journal of Pain, 18 Apr 2019. DOI: https://doi.org/10.1016/j.jpain.2019.04.005.
• Webster LR, Schmidt WK, Dilemma of Addiction and Respiratory Depression in the Treatment of Pain: A Prototypical Endomorphin as a New Approach, Pain Medicine, pnz122, https://doi.org/10.1093/pm/pnz122.
• Webster, L. Mobile Health Technology and Pain Management. The Research Post. September 1, 2022.