Long-acting OPIOID Analgesics for Non-cancer Pain

Oregon Health Resources Commission Long-acting OPIOID Analgesics for Non-cancer Pain Subcommittee Report Update #1, July, 2003 This report is an update of the initial Opioid Subcommittee Report of June 2002. All revisions are highlighted. Produced by: Health Resources Commission Kathleen Weaver, MD, Director Office for Oregon Health Policy & Research 255 Capitol Street NE Salem, OR 97310

Overview for Update #1 The 2001 session of the Oregon Legislature passed Senate Bill 819, authorizing the creation of a Practitioner-managed Prescription Drug Plan. The statute specifically directs the Health Resources Commission (HRC) to advise the Department of Human Services on this Plan. In January of 2002 the HRC appointed a subcommittee to perform an Evidencebased review of the use of long-acting opioids for non-cancer pain. Members of the subcommittee consisted of physicians, pharmacists, nurse practitioners, other health care professionals, consumers and advocates. The subcommittee had six meetings, two of which were general sessions of orientation and evidence-based analysis education. All meetings were held in public with appropriate notice provided. Subcommittee members worked with Oregon Health and Science University s Evidence-based Practice Center (OHSU-EPC) to develop and finalize key questions for drug class review, specifying patient populations, medications to be studied and outcome measures for analysis, considering both effectiveness and safety. Evidence was specifically sought for subgroups of patients based on race, ethnicity and age, demographics, other medications and co-morbidities. Using standardized methods, the EPC reviewed systematic databases, the medical literature and dossiers submitted by pharmaceutical manufacturers. Inclusion and exclusion criteria were applied to titles and abstracts, and each study was assessed for quality according to predetermined criteria. The OHSU-EPC report titled Drug Class Review on Opioid Analgesics for Noncancer Pain was completed the week of April 1, 2002, circulated to subcommittee members and posted on the web. The subcommittee met on April 10, 2002, to review the document. By consensus, the subcommittee members agreed to adopt the report. Time was allotted for public comment, questions and testimony. The subcommittee s meeting on April 24, 2002 was specifically scheduled to allow additional time for public testimony. All available sources of information; the EPC report, which includes information submitted by pharmaceutical manufacturers, and public testimony were considered. The conclusions drawn by the Opioid Subcommittee comprise the body of this report. Although cancer pain was not the purview of the subcommittee, the report, Management of Cancer Pain. Summary 1 funded by the Agency for Healthcare Research and Quality (AHRQ) and published January 2001, was also reviewed. The Opioid Subcommittee notes that the evidence analysis for cancer pain showed similar conclusions to those outlined below for non-cancer pain. 1 Management of Cancer Pain. Summary, Evidence Report/Technology Assessment: Number 35. AHRQ Publication No. 01-E033, January 2001. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/canpainsum.htm Oregon Health Resources Commission: OPIOID Update Report Page 2

In January of 2003 the HRC appointed an update committee to perform an evidence-based review of the June 2002 Long-Acting OPIOID Analgesics for Non-cancer Pain Subcommittee Report for new information or changes in the FDA package inserts. This report is an update of the initial June 2002 Opioid Subcommittee Report. All revisions are highlighted. Members of the Update Committee consisted of one HRC member, one Oregon State University (OSU) pharmacist, one OHPR physician, one OHSU-EPC physician, and two OPIOID Subcommittee members. The committee had one meeting held in public with appropriate notice provided. The Update Committee members worked with the OHSU-EPC reviewing the evidence for both effectiveness and safety. Evidence was specifically sought for subgroups of patients based on race, ethnicity, age, demographics, other medications and co-morbidities. The OHSU-EPC s update draft report, Update for long-acting opioids drug class review was completed April 2, 2003, circulated to Update Committee members and posted on the OHPR website at http://www.ohpr.state.or.us. The Update Committee met on May 5, 2003, to review the document and additional evidence. By consensus, the committee members agreed to adopt the EPC report. Time was allotted for public comment, questions and testimony. All available sources of information from the EPC s report that included information submitted by pharmaceutical manufacturers and public testimony, were considered. The Update Committee presented its findings to the HRC and the revisions were approved at its meeting on June 27, 2003. This report is prepared to facilitate the HRC in providing recommendations to OMAP for the plan drug list (PDL). This update report does not recite or characterize all the evidence that was discussed by the OHSU-EPC, the OPIOID Update Committee, or the HRC. For further information provided during the committee process readers are encouraged to review the source materials on the website. The OPIOID Committee of the HRC, working together with the EPC, OMAP, and the OSU College of Pharmacy, will continue to monitor medical evidence for new developments in this drug class. Approximately every six months emerging pharmaceuticals will be reviewed and if appropriate, a recommendation for inclusion in the PDL will be made. Significant new evidence for pharmaceuticals already on the PDL will be assessed and Federal Drug Administration (FDA) changes in indications and safety recommendations will be evaluated. The OPIOID Subcommittee Report will be amended if indicated. Substantive changes will be brought to the attention of the HRC, who may choose to approve the report, or reconvene the OPIOID Subcommittee. Oregon Health Resources Commission: OPIOID Update Report Page 3

This report and the OHSU-EPC s update draft report, Update on Drug Class Review on Long-Acting OPIOID Analgesics for Chronic Non-Cancer Pain are all available on the Office for Oregon Health Policy & Research, Practitioner- Managed Prescription Drug Plan website: www.oregonrx.org. Information regarding the HRC and its subcommittee policy and process can be found on the OHPR website: www.ohpr.state.or.us. More information, copies of the report, or minutes and tapes of the meetings can be requested from: Kathleen Weaver, MD Director, Health Resources Commission 255 Capitol St. NE, 5th Floor Salem, Oregon 97310 503-378-2422 ext. 406 Kathy.weaver@state.or.us Information dossiers submitted by pharmaceutical manufacturers are available upon request from OHSU-EPC by contacting: Jeani Crichlow Oregon Health & Science University Mailcode: BICC 3181 SW Sam Jackson Park Road Portland, OR 97201-3098 Phone: 503-494-4502 Fax: 503-494-4551 E-mail: crichlow@ohsu.edu There will be a charge for copying and handling in providing documents both from OHPR and OHSU-EPC. Critical Policy: Senate Bill 819 The Department of Human Services shall adopt a Practitioner-managed Prescription Drug Plan for the Oregon Health Plan. The purpose of the plan is to ensure that enrollees of the Oregon Health Plan receive the most effective prescription drug available at the best possible price. Health Resources Commission Clinical outcomes the most important indicators of comparative effectiveness ; Oregon Health Resources Commission: OPIOID Update Report Page 4

If evidence is insufficient to answer a question, neither a positive nor a negative association can be assumed. Inclusion Criteria: Scope Adult patients with (a) any non-cancer pain syndrome requiring chronic use of long-acting opioid medications (b) acute non-surgical/non-obstetric low back pain. Exclude: Cancer pain, acute pain other than low back pain. Definition of long-acting opioids for chronic pain: Morphine Sulfate (Morphine sulfate SA, Oramorph SR, MS Contin, Kadian, Avinza) Oxycodone (OxyContin) Methadone (Dolophine, others) Transdermal fentanyl (Duragesic) Levorphanol (Levo-Dromoran)0 Long-acting Codeine or Dihydrocodeine (not available in the U.S. at this time) Any other long-acting opioid identified (none) Key Questions: 1. What is the comparative efficacy of different long-acting opioid medications in reducing pain and improving functional outcomes in adult patients being treated for chronic non-cancer pain? 2. What is the comparative incidence and nature of adverse effects (including addiction and abuse) of long-acting opioid medications in adult patients being treated for chronic non-cancer pain? 3. Are there subpopulations of patients (specifically by race, age, sex or type of pain) with chronic non-cancer pain for which one long-acting opioid is more effective or associated with fewer adverse effects? New Findings of Opioid Update Committee 6/03 1. The EPC received dossiers from two manufacturers containing new information about evidence-based trial results that have become available since the completion of the initial report. Nine reports were from Janssen for Oregon Health Resources Commission: OPIOID Update Report Page 5

transdermal fentanyl and two were from Purdue Pharma for long acting oxycodone. 2. Kathy Ketchum, R.Ph., MPA:HA, OSU College of Pharmacy, reported the addition of one new long-acting opioid, Avinza. 3. Using the same search strategy as was used in the original long-acting opioids report, the EPC found 646 new citations. Only one was a new randomized trial of long-acting opioids in patients with non-cancer pain that was not included in the original report submitted April 2, 2002. Although this report by Caldwell JR et al. was included in the November 2002 revised "Drug Class Review on Long-Acting Opioid Analgesics for Chronic Non- Cancer Pain," it did not change any of the conclusions of that EPC Report. Another randomized controlled trial by Raja SN et al. was excluded in the EPC summary because the study design did not specify which long acting opioid was used in the intervention. A third open-label trial by Niemann et al. was too small a study (18 patients) focusing on a population with a disease (chronic pancreatitis) that is relatively uncommon and cannot be generalized to patients with other chronic pain conditions. In addition, in comparing transdermal fentanyl to long-acting morphine, the fentanyl group received increased doses above the manufacturer's recommended dose. 4. Only two new observational studies for comparative safety of transdermal fentanyl were identified by the EPC, but neither appeared to be a large, population-based study with rigorous adverse event assessment techniques, nor did they provide comparative data across different long acting opioids. 5. Update results from the Drug Abuse Warning Network (DAWN) reported increased numbers of oxycodone, hydrocodone and methadone mentions between 1994 to 2001. This study did not report the underlying clinical conditions of patients and did not distinguish between long- or short-acting and different modes of administration. It also did not evaluate overall use, which is necessary to assess comparative risk of various long-acting opioids. 6. The Addendum to the Opioid Subcommittee report was presented to the Health Resources Commission on May 23, 2003 where testimony was accepted from a concerned pain management physician who cited yet unpublished Oregon Health Division CD Summary that reported increased methadone deaths in Oregon over the preceding four years. The HRC requested further information. A report summarizing detailed information about methadone formulary inclusion, provider education on conversion to methadone, morbidity, and mortality from OMAP and the capitated health plans was presented to the HRC on June 27, 2003. Oregon Health Resources Commission: OPIOID Update Report Page 6

Amended Summary of Results (Changes highlighted) 1. WHAT IS THE COMPARATIVE EFFICACY OF DIFFERENT LONG-ACTING OPIOID MEDICATIONS IN REDUCING PAIN AND IMPROVING FUNCTIONAL OUTCOMES IN ADULT PATIENTS BEING TREATED FOR CHRONIC NON-CANCER PAIN? A. In head-to-head comparisons, has one or more long-acting opioid been shown to be superior to other long-acting opioids in reducing pain and improving functional outcomes when used for treatment of adults with refractory non-cancer pain? Two randomized trials provide the only direct evidence of the comparative efficacy of different long-acting opioids in chronic non-cancer pain. The first randomized trial compared transdermal Fentanyl to long-acting morphine in 256 patients. It was rated poor quality. Results were conflicting with improved pain control with Fentanyl but also increased adverse reactions to Fentanyl. The second fair-quality randomized trial compared once-daily morphine to twice-daily morphine and found similar efficacy. By consensus, the subcommittee agrees that there is no comparative evidence that supports a difference between longacting opioids in reducing pain and improving functional outcomes. B. In trials comparing long-acting opioids to other types of drugs or to placebo, is there a pattern to suggest that one long-acting opioid is more effective than another? Seven studies compared long-acting opioids to short acting opioids; another seven, long-acting opioids to non-opioids or placebo. All trials were rated as fair quality. The trials were difficult to compare, but did not suggest any agent as being superior in efficacy or lower in adverse reactions. By consensus, the subcommittee finds that there is no evidence that any long-acting opioid has been shown to be superior in comparing long-acting opioids to other types of drugs. Oregon Health Resources Commission: OPIOID Update Report Page 7

C. Have long-acting opioids been shown to be superior to short-acting opioids in reducing pain and improving functional outcomes when used for treatment of adults with chronic non-cancer pain? Seven fair quality trials directly compared long-acting and short-acting agents. There is no evidence to suggest that long-acting agents are superior to shortacting agents. A fair quality study found a significant difference in terms of sleep scores. The finding might be invalidated by baseline differences in the treatment groups. The subcommittee finds that long-acting opioids may improve sleep compared to short-acting opioids. There is no comparison study measuring sleep scores between different long-acting opioids. 2. WHAT IS THE COMPARATIVE INCIDENCE AND NATURE OF ADVERSE EFFECTS (INCLUDING ADDICTION AND ABUSE) OF LONG-ACTING OPIOID MEDICATIONS IN ADULT PATIENTS BEING TREATED FOR CHRONIC NON-CANCER PAIN? A. In head-to-head comparisons, has one or more long-acting opioid been shown to be associated with fewer adverse events compared to other long-acting opioids when used for treatment of adults with chronic noncancer pain? In the trial noted above comparing two long-acting opioids, the rate of withdrawal favored long-acting morphine but the trial was rated poor quality for adverse events and did not assess rates of addiction or abuse. The subcommittee finds by consensus that no evidence by comparative trials supports a difference in the incidence and nature of adverse effects, including addiction and abuse. B. In trials comparing long-acting opioids to other types of drugs or to placebo, is there a pattern to suggest that one long-acting opioid is associated with fewer adverse events than another? In the thirteen fair to poor quality trials, meaningful comparisons were difficult to make and no pattern for any drug could be established regarding adverse effects. Rates of abuse and addiction were not reported. Observational studies were of poor quality and did not provide additional evidence. Oregon Health Resources Commission: OPIOID Update Report Page 8

The subcommittee finds by consensus that studies comparing long-acting opioids to other types of drugs do not show any evidence to support that any long-acting opioid has fewer adverse effects, including abuse and addiction, than any other longacting opioid. C. Have long-acting opioids been shown to have fewer adverse events than short-acting opioids when used for treatment of adults with chronic noncancer pain? The seven trials referenced in #1B reveal no pattern favoring long or shortacting opioids for any adverse events. The subcommittee agrees by consensus that there is no evidence to show that long-acting opioids have fewer adverse effects than short-acting opioids. 3. ARE THERE SUB-POPULATIONS (SPECIFICALLY BY RACE, AGE, SEX OR TYPE OF PAIN) WITH CHRONIC NON-CANCER PAIN FOR WHICH ONE LONG-ACTING OPIOID IS MORE EFFECTIVE OR ASSOCIATED WITH FEWER ADVERSE EFFECTS? No trials or observational studies were designed to evaluate opioids with respect to use in different races, ethnicity, age groups, or gender. The few trials evaluating types of chronic pain did not provide sufficient evidence to establish significant differences between long-acting opioids. The sub-committee agrees by consensus that there is insufficient evidence to draw any conclusions about the comparative effectiveness, incidence and nature of adverse effects including addiction and abuse, of long- acting opioids by age or gender or by differing racial and ethnic populations. Conclusion (no changes) In a series of public meetings with the opportunity for public questions, comment and testimony, the Opioid Subcommittee of the Health Resources Commission reviewed the medical evidence comparing long-acting opioids for non cancer pain. All available sources of information including OHSU s Evidence-based Oregon Health Resources Commission: OPIOID Update Report Page 9

Practice Center report: Drug Class Review on Opioids Analgesics for Noncancer Pain, and additional information presented in public testimony were considered. Using all available sources of information, the subcommittee arrived at the following conclusions about the comparative effectiveness and safety of long-acting opioid analgesics as supported by analysis of the medical literature: It is the decision of the HRC Opioid Subcommittee that there is insufficient evidence to draw any conclusions about the comparative effectiveness of long-acting opioids. There is also insufficient evidence to draw conclusions about incidence and nature of adverse effects, including discontinuation rates and addiction and abuse of long-acting opioids. No evidence supports differences in efficacy or adverse effects in sub-populations by race and ethnicity, age, gender, or type of pain in this class of drugs. Even though evidence does not demonstrate a difference between long-acting opioids or between long-acting opioids when compared to other drugs, limitations of studies currently available for review preclude a confident conclusion that no differences exist. It is possible that better constructed studies may yet demonstrate such differences. Oregon Health Resources Commission: OPIOID Update Report Page 10

Frank Baumeister, Jr., MD Chair, Health Resources Commission Diane Lovell Vice Chair, Health Resources Commission Bruce Goldberg, MD Administrator Office for Health Policy & Research Steven DeLashmutt, MD Chair, OPIOID Update Committee Kathleen Weaver, MD Director. Health Resources Commission Office for Health Policy & Research Health Resources Commission Brad Bowman, MD Steven DeLashmutt, MD Elaine Dunda Dean Haxby, Pharm. D. Dan Kennedy, R.Ph Paul R. Tiffany Walter Shaffer, MD Joanna Zamora, RN OPIOID Update Committee Members Kathleen Weaver, MD Steve DeLashmutt, MD Roger Chou, MD Kathy Ketchum, R.Ph., MPA:HA William Origer, MD William Petty, MD Opioid Analgesics for Non-Cancer Pain Subcommittee Members Peter Kosek, MD William Petty, MD Eric Schnebly, PharmD Peter Rasmussen, MD Sue Millar, PharmD Joanne Brayden Yung K. Kho, MD Annette Gravem, RN Kenneth Bizovi, MD David Balmer, MD William Origer, MD Joseph Dunn, MD Oregon Health Resources Commission: OPIOID Update Report Page 11

Health Resources Commission The State of Oregon s Health Resources Commission is a volunteer Commission appointed by the Governor. The Health Resources Commission provides a public forum for discussion and development of consensus regarding significant emerging issues related to medical technology. Created by statute in 1991, it consists of four physicians experienced in health research and the evaluation of medical technologies and clinical outcomes; one representative of hospitals; one insurance industry representative; one business representative; one representative of labor organizations; one consumer representative; two pharmacists. All Health Resources Commissioners are selected with conflict of interest guidelines in mind. Any minor conflict of interest is disclosed. The Commission is charged with conducting medical assessment of selected technologies, including prescription drugs. The Commission may use advisory committees or subcommittees, the members to be appointed by the chairperson of the Commission subject to approval by a majority of the Commission. The appointees have the appropriate expertise to develop a medical technology assessment. Subcommittee meetings and deliberations are public, where public testimony is encouraged. Subcommittee recommendations are presented to the Health Resources Commission in a public forum. The Commission gives strong consideration to the recommendations of the advisory subcommittee meetings and public testimony in developing its final reports. Oregon Health Resources Commission: OPIOID Update Report Page 12