AJA Asian Journal of Anesthesiology

Advancing, Capability, Improving lives

Short communication
Volume 53, Issue 2, Pages 77-79
Jack E.Henningfield 1 , Wei-ZenSun 2
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Abstract

In this commentary on the medical use and regulation of transdermal buprenorphine we bring together our complimentary perspectives on the neuropharmacology of analgesics (Dr. Henningfield) and clinical medicine to address the needs of people with pain (Dr. Sun). Together, the neuropharmacology of buprenorphine, the clinical and abuse deterring benefits of the 7-day transdermal formulation, the low rates of harmful use and abuse detected in post-marketing surveillance studies, and the desirable clinical benefits in the elderly, in persons with compromised kidney function, and other populations support the regulation of buprenorphine comparable to tramadol-like analgesics. We support this approach and believe that it strikes the right balance of control to provide appropriate access to people with pain and their health providers, while still providing the basis for deterring harmful use and abuse.

Keywords

buprenorphine; transdermal; regulation; dependence; pain;


In this commentary on the medical use and regulation of transdermal buprenorphine we bring together our complimentary perspectives on the neuropharmacology of analgesics (Dr. Henningfield) and clinical medicine to address the needs of people with pain (Dr. Sun). The article by Pergolizzi et al. summarizes much of the basic and clinical science of buprenorphine, including as formulated in the 7-day transdermal product that has been approved by many regulatory agencies worldwide since the early 2000s.1Neuropharmacology research and clinical studies demonstrate that the analgesic efficacy of transdermal buprenorphine is similar to morphine-like opioids, however, its dependence potential and actual rates of harmful use and overdose are more similar to tramadol.1 The implications of these findings for the regulation of transdermal buprenorphine are discussed in this editorial.a

The regulation of drugs with a potential to be harmfully misused and to produce dependence is among the most challenging and delicate balancing acts in drug regulation because it has far-reaching consequences in the daily lives of people with pain as well as from the broad public health perspective of harmful drug use, dependence, and drug overdose.2345 Furthermore, ensuring appropriate access to pain medications is considered an issue of human rights by the World Health Organization.34

When access to medications is overly restricted, those who suffer the most are often people with pain, whereas opioid abusers simply turn to other sources such as illicit heroin and opium.56 In the United States, where harmful use of prescription drugs and heroin are major public health problems, part of the solution is to enable appropriate access to opioid analgesics for medical use, while encouraging the development of less abusable opioids and increasing access to treatment of opioid abusers with less abusable opioids such as buprenorphine.578 Therefore, it is important to find the right balance in drug control to provide sufficient access to enable the ethical and medically beneficial treatment of people with pain as intended by the International Drug Control Conventions.34 This includes chronic noncancer pain, which can be as devastating as the pain associated with cancer, and afflicts more people than those suffering with cancer-related chronic pain.12491011

The regulation of dependence producing drugs is guided by more than a half century of scientific study that provides validated scientific methods used to study medications and guide their regulation.71213 As discussed in the foregoing reviews and guidance documents, the scientific foundation of controlled drug regulation is an understanding of the chemistry and pharmacology of the drug and the impact of the formulation on its safety and propensity for harmful use and dependence.

The search for less addicting opioid analgesics became an increasingly prominent area of pharmaceutical development by the mid-20th century and buprenorphine was an important product of this research. Its favorable safety profile and relatively low dependence potential profile heralded it as an important advance in analgesia and addiction medicine by NIDA as well as clinicians and researchers.51415 By 1978, this research led NIDA's lead dependence potential researcher, and then the Director of the NIDA Addiction Research Center, Dr. Donald R. Jasinski to issue the following statement: “In conclusion, buprenorphine has a unique pharmacology with immediately obvious therapeutic applications as an analgesic of low abuse potential…”.14

More than three decades of additional research and one quarter century of clinical experience confirm that Dr. Jasinski's appraisal was correct. The drug, in the form of an injectable analgesic, was placed in the least restrictive drug schedule in the US for controlled substances when it was approved in 1981. The additional benefits of a transdermal formulation from the perspectives of clinical therapeutics and harmful use were not anticipated at that time because such delivery systems had not yet been approved for use for opioids. By the 1990s, however, transdermal drug delivery systems were increasingly used across a broad range of drugs due to their advantages with respect to therapeutic drug delivery, patient compliance, and safety.

Clinical studies in the early 2000s revealed that extended release transdermal buprenorphine was an important advance in opioid delivery because it combines a molecule with a good analgesic profile and relatively low abuse potential and a formulation that provides seven days of stable pain relief thus minimizing the cycles of sedation and pain that appear more prominently with short acting opioid medications as discussed by Pergolizzi et al. in this issue.113 Additional clinical benefits include low sedation, low respiratory depression, good tolerability for people with compromised kidney function, and particular benefits for elderly populations such as the fact that it does not require dosage adjustments.115

The relatively low potential for harmful use and dependence compared to morphine-like opioids results from both the pharmacology of buprenorphine and harmful use deterring effects of the transdermal system. Specifically, buprenorphine is characterized by (1) “ceiling euphoriant” effects that reduce its attractiveness to persons who abuse drugs; (2) a low withdrawal severity profile, and (3) low reinforcing properties in animal and human studies compared to morphine-like opioids.115 Extensive post-marketing surveillance in the US and other countries show that the actual abuse of transdermal buprenorphine is very low compared to morphine-like opioids.115

We have focused our comments on opioid medications, however, it is important to recognize that pain is most effectively treated by comprehensive or multimodal pain management approaches which recognize the biopsychosocial model of pain.12 In this context, pain management may include behavioral therapies including exercise, yoga, massage therapy and acupuncture and other traditional strategies.2916 Such approaches can be used along with medications, in some cases in place of mediations, and for some patients as long term pain management approaches if medication administration is discontinued.216 The important concept is to recognize individual patient needs and the importance of comprehensive pain management.

Together, the neuropharmacology of buprenorphine, the clinical and abuse deterring benefits of the 7-day transdermal formulation, the low rates of harmful use and abuse detected in post-marketing surveillance studies, and the desirable clinical benefits in the elderly, in persons with compromised kidney function, and other populations support the regulation of buprenorphine comparable to tramadol-like analgesics. Consistent with these observations, transdermal buprenorphine is regulated similarly to tramadol in the United Kingdom, China, and also recently in Taiwan, consistent with international scheduling by the WHO and the International Narcotics Control Board, which controls buprenorphine under the 1971 Psychotropic convention as a Schedule III drug.b We support this approach and believe that it strikes the right balance of control to provide appropriate access to people with pain and their health providers, while still providing the basis for deterring harmful use and abuse.

Disclosure

Dr. Henningfield provides consulting services through PinneyAssociates on drug dependence potential assessment and regulation and this has included speaking on accessibility of analgesia at conferences and meetings funded by Mundipharma.

Dr. Wei-Zen has no activities to disclose.

Conflict of interest

No conflict of interest to declare.

Financial support

Dr. Henningfield has received no specific financial support for preparation of this manuscript beyond his general salary at Pinney Associates.

Dr. Wei-Zen has received no specific financial support for preparation of this manuscript.

This manuscript is based on the presentation by Dr. Henningfield at the Controlled Drug Forum in Taipei, September 26th, 2014 and the 2014 Annual Meeting of the Taiwan Society of Anesthesiologists in Taichun, September 27th, 2014.

a

This editorial is dedicated to Dr. Henningfield’s mother, Vivian P. Henningfield (1921–2014) who was treated with opioids as needed for her moderate to sometimes severe chronic non-cancer pain related to arthritis, injury and increasing heart and renal failure. This treatment enabled her to continue her volunteer work into her 9th and 10th decades of life including grand mothering efforts for abused and substance abusing young women in a care center, making hand cut cards with uplifting and spiritual verses for those in need, and remaining socially active and contributing to her family and community until her last week of life when she died in peace.

b

Note that in the US buprenorphine was originally placed in the least restrictive of all drug schedules when it was approved as a parenteral analgesic in 1985. All forms of buprenorphine were scheduled somewhat more restrictively (CIII) in 2001 when the very high oral dosage form was approved for the treatment of persons known to abuse opioids. The drug control system in the US generally schedules drugs on the basis of the most abuseable form of the chemical entity and rarely gives consideration to the potential abuse deterring effects of the formulation for scheduling placement.


References

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Pergolizzi JV, Scholten W, Smith KJ, Leighton-Scott J, Willis JC, Henningfield JE.
The unique role of transdermal buprenorphine in the global chronic pain epidemic. Acta Anaesthesiol Taiwan, current issue.
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Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction
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References

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