Comparative efficacy and safety of long-acting oral opioids for chronic non-cancer pain: a...

1026 Journal of Pain and Symptom Management Vol. 26 No. 5 November 2003

Review Article

Comparative Efficacy and Safetyof Long-Acting Oral Opioids for ChronicNon-Cancer Pain: A Systematic ReviewRoger Chou, MD, Elizabeth Clark, MD, MPH, and Mark Helfand, MD, MPHDepartments of Medicine (R.C., M.H.) and Family Medicine (E.C.), Oregon Health & ScienceUniversity; Oregon Evidence-Based Practice Center (R.C., M.H., E.C.); and Portland VeteransAffairs Medical Center (M.H.), Portland, Oregon, USA

AbstractOpioids have been endorsed as appropriate treatment for refractory chronic non-cancer painwhen used according to published guidelines. They are widely used for this indication.However, there appear to be gaps in our understanding of the efficacy and safety ofindividual long-acting opioids compared to each other or as a class compared to short-acting opioids. This systematic review summarizes and assesses the evidence for thecomparative efficacy and safety of long-acting opioids in the management of chronic non-cancer pain. Randomized trials (for comparative efficacy and adverse events) andobservational studies (for adverse events only) that included non-parenteral long-actingopioids were sought using electronic databases, handsearching reference lists, and solicitingpharmaceutical company submissions. Searches were performed through October 2002. Thevalidity of each included study was assessed using a data abstraction form and predefinedcriteria. An overall grade was allocated for the body of evidence for each key question. Atotal of 16 randomized trials (comparative efficacy and adverse events), enrolling 1427patients, and 8 observational studies (adverse events) of 1190 patients were included inthis review. No randomized trial was rated good quality; observational studies weregenerally of poorer quality than the trials. There was insufficient evidence to prove thatdifferent long-acting opioids are associated with different efficacy or safety profiles. Therewas also insufficient evidence to determine whether long-acting opioids as a class are moreeffective or safer than short-acting opioids. A subgroup of three studies on long-actingversus short-acting oxycodone was more homogeneous and provided fair evidence that theseformulations are equally effective for pain control. J Pain Symptom Manage2003;26:1026–1048. � 2003 U.S. Cancer Pain Relief Committee. Published by ElsevierInc. All rights reserved.

Key WordsAnalgesics, opioid, pain, meta-analysis, fentanyl, morphine, oxycodone, codeine

Address reprint requests to: Roger Chou, MD, 9721 SWMorrison St., Portland, OR 97225, USA.Accepted for publication: March 18, 2003.

� 2003 U.S. Cancer Pain Relief CommitteePublished by Elsevier Inc. All rights reserved.

Note: Evidence tables and appendices are avail-able on the website http://www.oregonrx.org/OrgrxPDF/Opioid%20Review.htm (last updated April2002) or from the authors (updated October 2002).

0885-3924/03/$–see front matterdoi:10.1016/j.jpainsymman.2003.03.003

Vol. 26 No. 5 November 2003 1027Long-Acting Oral Opioids for Chronic Non-Cancer Pain

IntroductionChronic pain, typically defined as pain of at

least 6 months’ duration, is a common causeof major disability. It is estimated that 1 in 5adult Americans, or 30 million people, experi-ence chronic pain.1 Chronic non-cancer painafflicts a significant subset of chronic pain pa-tients, causing personal suffering, reduced pro-ductivity, and substantial health care costs.2

Opioids have been endorsed by the AmericanAcademy of Pain Medicine and the AmericanPain Society3 as appropriate treatment for re-fractory chronic non-cancer pain in the generalpopulation as well as in older patients,4 whenused judiciously and according to guidelinessimilar to those used for cancer patients.

Opioids are a class of medications that acton common receptors and are natural deriva-tives of morphine.5 They are the most potentmedications available for treatment of mosttypes of severe pain. They are also associatedwith a variety of adverse events, including abuseand addiction. Opioids are available in bothshort- and long-acting preparations, and the useof long-acting opioids for patients with chronicnon-cancer pain has become common. Becausechronic pain may not resolve over time, use ofopioid analgesics for these conditions can belong-term. Despite the widespread use of long-acting opioids, there are few data regarding thecomparative efficacy and adverse event profilesassociated with specific long-acting opioids inpatients who have chronic non-cancer pain.6

In 2001, the Oregon Legislature passedSenate Bill 819, which mandated the develop-ment of a Practitioner-Managed PrescriptionDrug Plan (PMPDP) for the Oregon HealthPlan (OHP). The Oregon Health Plan refersto a collective series of laws enacted from 1989through 1995 that sought to expand Medicaidcoverage to low-income Oregonians by creatingstate-run insurance pools, enacting insurancereforms, using a federal waiver that allowed forMedicaid expansion, and excluding certain di-agnoses and treatments from coverage. As partof this process for developing a PMPDP forthe Oregon Health Plan, the Oregon HealthResources Commission (OHRC) required thatan evidence-based review of the state’s most ex-pensive drug classes be performed. The OHRCrequested a review of the long-acting opioiddrug class specifically in persons with chronic

non-cancer pain. The OHRC requested infor-mation about whether there is evidence thatone or more long-acting opioid is superior toothers in terms of efficacy and safety, andalso whether long-acting opioids as a class aremore efficacious or safer than short-acting opi-oids in the treatment of chronic non-cancerpain.

Scope and Key QuestionsThe scope of the review and key questions

were developed and refined with input from anOHRC subcommittee comprised of statewideexperts (pharmacists, primary care clinicians,pain care specialists, and representatives of thepublic). In consultation with the subcommit-tee, we selected the following key questions toguide the review:

1. What is the comparative efficacy of differ-ent long-acting opioids in reducing painand improving functional outcomes inadult patients being treated for chronicnon-cancer pain?

A. In head-to-head comparisons, hasone or more long-acting opioidbeen shown to be superior to otherlong-acting opioids in reducingpain and improving functional out-comes when used for treatment ofadults with chronic non-cancerpain?

B. In trials comparing long-acting opi-oids to other types of drugs or toplacebo, is there a pattern to suggestthat one long-acting opioid is moreeffective than another?

C. Have long-acting opioids beenshown to be superior to short-actingopioids in reducing pain and im-proving functional outcomes whenused for treatment of adults withchronic non-cancer pain?

2. What are the comparative incidence andnature of adverse effects (including addic-tion and abuse) of long-acting opioidmedications in adult patients beingtreated for chronic non-cancer pain?

A. In head-to-head comparisons, hasone or more long-acting opioidbeen shown to be associated with

1028 Vol. 26 No. 5 November 2003Chou et al.

fewer adverse events compared toother long-acting opioids whenused for treatment of adults withchronic non-cancer pain?

B. In trials comparing long-acting opi-oids to other types of drugs or toplacebo, is there a pattern to suggestthat one long-acting opioid is associ-ated with fewer adverse eventsthan another?

C. Have long-acting opioids beenshown to have fewer adverse eventsthan short-acting opioids when usedfor treatment of adults with chronicnon-cancer pain?

3. Are there subpopulations of patients (spe-cifically by race, age, sex, or type of pain)with chronic non-cancer pain for whichone long-acting opioid is more effectiveor associated with fewer adverse effects?

Several aspects of the key questions deservecomment:

Population. The population included in thisreview is adult (greater than 18 years old) pa-tients with chronic non-cancer pain. We de-fined chronic non-cancer pain as continuousor recurring pain of at least 6 months’ duration.Senate Bill 819 specifically excludes cancer pa-tients and patients with HIV from the PMPDPprocess, and they were not part of this review.

Drugs. We included oral or transdermal long-acting opioids. “Long-acting” was defined asopioids administered twice a day or less fre-quently. Long-acting opioids that we identifiedwere transdermal fentanyl and oral oxycodone,morphine, methadone, levorphanol, codeine,and dihydrocodeine. “Short-acting” wasdefined as opioids administered more fre-quently than three times a day. Although “sus-tained-release” and “immediate-release” areother terms used to describe the onset and du-ration of action of certain opioid preparations,for this review we classified opioids on thebasis of dosing frequency.

Outcomes. The main efficacy measures werepain intensity, pain relief, and function. There isno single accepted standard regarding how tomeasure these outcomes.

Most studies measure pain intensity usingeither visual analogue or categorical pain scales.Visual analogue scales (VAS) consist of a lineon a piece of paper labeled 0 at one end, indi-cating no pain, and a maximum number (com-monly 100) at the other, indicating excruciatingor most severe pain. Patients designate theircurrent pain level on the line. An advantage ofVAS is that they provide a continuous rangeof values for relative severity. A disadvantage isthat the meaning of a pain score for any individ-ual patient remains arbitrary. Categorical painscales, on the other hand, consist of severalpain category options from which a patientmust choose (e.g., no pain, mild, moderate, orsevere). A disadvantage of categorical scales isthat patients must chose between categories thatmay not accurately describe their pain. Thebest approach may be to utilize both methods.7

Pain control (improvement in pain) and painrelief (resolution of pain) are also measuredusing visual analogue and categorical scales.

Studies usually evaluate function using theMedical Outcomes Study Short Form-36 (SF-36), Short Form-12 (SF-12), or another multi-question assessment. These questionnairesmeasure how well an individual functions physi-cally, socially, cognitively, and psychologically.Another approach to measuring function is tofocus on how well the medication helps prob-lems in daily living commonly faced by patientswith chronic pain, such as getting enough sleepor staying focused on the job. Some studies alsoreport effects on mood and the preference forone medication over another.

The subcommittee selected the following ad-verse events for our review: abuse, addiction,respiratory depression, nausea, vomiting, con-stipation, dizziness, somnolence, and confu-sion. These were the adverse events felt bythe subcommittee to be the most common ortroubling adverse events in clinical practice. Werecorded rates of these adverse events as wellas rates of discontinuation due to a particularadverse effect. In some studies, only “serious”adverse events or adverse events “thought re-lated to treatment medication” are reported.Many studies do not define these terms.

The subcommittee specifically requested thatwe examine whether opioids differ in the riskof abuse and addiction. Although standardizeddefinitions for abuse and addiction have been


proposed, they have not been consistently uti-lized in studies investigating this outcome.8,9

We recorded any information about abuse andaddiction, including rates of death and hospital-ization when available.

Because of inconsistent reporting of out-comes, withdrawal rates may be a more reliablemeasure in studies of opioids. This outcome maybe a surrogate measure for either clinical effi-cacy or adverse events. One trial that examinedreason for withdrawal found different reasonsin its arms: withdrawals were due to adverseevents in patients on long-acting oxycodone, butdue to inadequate pain control in the patientson placebo.10 High withdrawal rates probablyindicate some combination of poor tolerabil-ity and ineffectiveness. An important subset iswithdrawal due to any adverse event (those whodiscontinue specifically because of adverseeffects).

Study Types. We included controlled clinicaltrials to evaluate efficacy. The validity of con-trolled trials depends on how they are designed.Randomized, properly blinded clinical trials areconsidered the highest level of evidence forassessing efficacy.11–13 Clinical trials that are notrandomized or blinded, and those that haveother methodologic flaws, are less reliable, butare also discussed in our report.

Trials that evaluated one long-acting opioidagainst another long-acting opioid provideddirect evidence of comparative efficacy andadverse event rates. Trials that compared long-acting opioids to short-acting opioids, non-opioids, or placebos provided indirectcomparative data.

To evaluate adverse event rates, we includedclinical trials and observational cohort studies.Clinical trials are often not designed to assessadverse events, and may select patients at low-risk for adverse events (in order to minimizedropout rates) and utilize methodology inad-equate for assessing adverse events. Observa-tional studies designed to assess adverse eventrates may include broader populations, carryout observations over a longer time period, uti-lize higher quality methodologic techniques forassessing adverse events, or examine largersample sizes.

One unique issue that complicates the inter-pretation of studies of chronic pain is “incom-plete cross-tolerance.” In medical jargon, a

patient who finds that a particular opioid isless effective over time is said to have become“tolerant” to that drug. “Incomplete cross-toler-ance” means that a patient’s “tolerance” for oneopioid may not carry over to other opioids. Ac-cording to the theory of incomplete cross-toler-ance, individuals who have been taking oneopioid may do better if they switch to a differentopioid (“opioid rotation”)—not because thenew one is a better drug, but simply because itis not the one they have been taking. In observa-tional studies of both cancer and non-cancerpatients, there is some evidence that incom-plete cross-tolerance occurs.14–17 In some cases,opioid rotation may be done to minimize ad-verse events.

MethodsLiterature Search

To identify articles relevant to each key ques-tion, we searched, in order, the Cochrane Li-brary (2002, Issue 1), MEDLINE (1966–2002),EMBASE (1980–2001), and reference lists ofreview articles. In electronic searches, we com-bined terms for pain with terms for opioid anal-gesics and narcotics, and relevant researchdesigns (see Appendix A for complete searchstrategy). In addition, the State of Oregon cre-ated and disseminated a submission protocolto pharmaceutical manufacturers for the sub-mission of clinical and economic evaluationdata to the Evidence-Based Practice Center. Allcitations were imported into an electronic data-base (EndNote 5.0). Searches on the electronicdatabases were carried out through October2002, using updates on electronic databasesafter the initial searches.

Study SelectionAll English-language titles and abstracts and

suggested additional citations were reviewed forinclusion using criteria developed by the re-search team with input from the subcommit-tee. We obtained full-text articles if the title andabstract review met the following eligibilitycriteria:

1. Systematic reviews of the clinical efficacyor adverse event rates of long-acting opi-oids in patients with chronic non-cancerpain, OR


2. Randomized controlled trials that com-pared one of the long-acting opioids listedabove to another long-acting opioid, ashort-acting opioid, a non-opioid, orplacebo in adult patients with chronicnon-cancer pain, OR

3. Randomized controlled trials and observa-tional studies that reported adverse eventrates for one of the long-acting opioidslisted above.

We re-applied these eligibility criteria to thefull-text articles, ensuring that the clinical effi-cacy or adverse event rates from specific opioidswere reported or could be calculated. Althoughstudies of longer duration were preferred, wehad no lower limit on the length of follow-up,but excluded “single-dose studies,” which exam-ine the effects of a single dose of medicationrather than a course of treatment.

Searches identified 3495 citations: 1081 fromthe Cochrane Library, 1106 from Medline, 1205from EMBASE, 42 from reference lists, and60 from pharmaceutical company submissions.We identified 1226 clinical trials and excluded1195 of these (see Appendix C for detailedsearch results). Nine hundred twenty-two clini-cal trials were excluded because they did notevaluate an included population (most ex-cluded studies evaluated patients with acutepain or cancer pain), 252 were excludedbecause they did not evaluate an included inter-vention (long-acting opioid), and 22 were ex-cluded because they did not evaluate anincluded outcome (pain control, pain relief,or function). Thirty-one trials were retrievedfor more detailed evaluation. After this sec-ond review, we excluded 14 trials: 10 becausethey did not evaluate an included interventionand 4 because they did not evaluate an includedpopulation. One additional randomized trialwas excluded because it used either long-actingmorphine or oxycodone in its opioid interven-tion group, and did not provide separate resultsfor each long-acting opioid.18 Sixteen random-ized controlled trials provided usable data andare included in evidence tables. We also re-viewed eight observational studies that evalu-ated adverse event rates from long-actingopioids.

Data AbstractionOne reviewer abstracted the following data

from included trials: study design, setting, pop-ulation characteristics (including sex, age, race,

diagnosis), eligibility and exclusion criteria, in-terventions (dose and duration), comparisons,numbers screened, eligible, enrolled, and lostto follow-up, method of outcome ascertain-ment (e.g., scales used), and results for eachoutcome. Although there is no clear consensuson “true” equianalgesic doses of opioid medica-tions, equianalgesic doses were estimated usingpublished tables.19 We recorded intention-to-treat results if available and the trial did notreport high overall loss to follow-up. In trialswith crossover, because of the potential for dif-ferential withdrawal prior to crossover biasingsubsequent results, outcomes for the first inter-vention were recorded if available. A secondreviewer checked all data.

Quality AssessmentWe assessed quality of trials based on the pre-

defined criteria listed in Appendix B. We ratedthe internal validity of each trial based on themethods used for randomization, allocationconcealment, and blinding; the similarity ofcompared groups at baseline; maintenance ofcomparable groups; adequate reporting of drop-outs, attrition, crossover, adherence, and con-tamination; loss to follow-up; and the use ofintention-to-treat analysis. External validity oftrials was assessed based on adequately describ-ing the study population, similarity of patientsto other populations to whom the interventionwould be applied, control group receiving com-parable treatment, funding source, and role ofthe funder.

Overall quality was assigned based on criteriadeveloped by the US Preventive Services TaskForce and the National Health Service Centerfor Reviews and Dissemination (UK).11,12 Trialsthat had a fatal flaw in one or more catego-ries were rated poor-quality; trials that met allcriteria were rated good-quality; the remainderwas rated fair-quality. As the “fair-quality” cate-gory is broad, studies with this rating vary intheir strengths and weaknesses: the results ofsome fair-quality studies are unlikely to be valid,while others are probably or likely to be valid. A“poor-quality” trial is not valid—the results areat least as likely to reflect flaws in the studydesign rather than true differences between thecompared drugs. A particular randomized trialmight receive two different ratings: one for effi-cacy and another for adverse events.


Appendix D shows the criteria we used torate clinical trials and observational studies ofadverse events. These criteria reflect aspectsof the study design that are particularly im-portant for assessing adverse event rates. Werated observational studies as good quality foradverse event assessment if they adequately metsix or more of the seven pre-defined criteria,fair if they met three to five criteria, and poorif they met two or fewer criteria.

After assignment of quality ratings by the ini-tial reviewer, quality ratings were independentlyassigned by a second reviewer. Overall qualityrating and quality rating scores (for studies onadverse event assessment) were compared be-tween reviewers. If overall quality ratings dif-fered, the two reviewers came to consensusprior to assigning a final quality rating.

Data SynthesisWe constructed evidence tables showing the

study characteristics, quality ratings, and resultsfor all included studies.

To assess the overall strength of evidence fora body of literature about a particular key ques-tion, we examined the consistency of study de-signs, patient populations, interventions, andresults. Consistent results from good-qualitystudies across a broad range of populationswould suggest a high degree of certainty thatthe results of the studies were true (that is, theentire body of evidence would be considered“good quality.”) For a body of fair-quality stud-ies, however, consistent results may indicate thatsimilar biases are operating in all the studies.

ResultsOverview of Included Trials

We identified 16 randomized trials (1427 pa-tients enrolled) that evaluated long-acting opi-oids in chronic non-cancer pain populations(Table 1). Recent non-systematic reviews on ad-verse events from opioids have identified onlytwo trials each.2,6 We did not find a relevantsystematic review for any of the key questions.

Only two of the 16 trials compared one long-acting opioid to another.20,21 One of thesetrials20 compared transdermal fentanyl to long-acting morphine; the other21 compared a once-daily morphine preparation to a twice-dailymorphine preparation. Seven trials compared a

long-acting opioid to a short-acting opioid,22–28

and seven compared a long-acting opioid to anon-opioid or placebo.10,29–34 Seven trials useda crossover design.20,24,25,29,31,32,34 We identi-fied trials on long-acting oxycodone,10,23,25,28,34

long-acting morphine,20,21,26,30–32 long-actingdihydrocodeine,24,27 long-acting codeine,22,29,33

and transdermal fentanyl.20 We did not identifyany trials on levorphanol or methadone. Onesmall trial35 with a high rate of withdrawal (14/20) cited in reference lists2,29 could not be lo-cated despite searches for journal, title, andauthor.

The trials ranged in size from 1231 to 29521

evaluable enrollees, with an average of 79 en-rollees. Five of the trials focused on osteoarthri-tis,10,21,23,27,33 five on back pain,22,24–26,28 two onneuropathic pain,30,34 one on phantom limbpain,31 and three on heterogeneous chronicnon-cancer pain.20,29,32

All of the trials were of relatively short dura-tion, ranging from 5 days22 to 16 weeks.26 Alltrials excluded persons with past or current sub-stance abuse. The majority of trials recruitedpatients from specialty clinics, most commonlyfrom rheumatology or pain practices. Race wasrarely reported. Sex had a slight predominance(slightly greater than 50%) towards women.The average age of enrollees was 55.

Assigned quality ratings did not differ be-tween reviewers.

Key Question Outcomes1A. In head-to-head comparisons, has one or

more long-acting opioid been shown to be supe-rior to other long-acting opioids in reducingpain and improving functional outcomes whenused for treatment of adults with refractorynon-cancer pain?

Two trials directly compared the efficacy ofone long-acting opioid to another in chronicpain of non-cancer origin.20,21 One trial20 com-pared transdermal fentanyl to long-acting mor-phine twice a day. The other trial21 compareda once-daily morphine preparation to a twice-daily morphine preparation.

The study that compared transdermal fen-tanyl to oral long-acting morphine used acrossover design in a population of 256 hetero-geneous chronic pain patients with an averageduration of 9 years pain.20 This study wasrated poor quality because of several major


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methodologic flaws (Evidence Table 1.1). Themost important areas of concern were that nei-ther patients nor investigators were blinded,and many of the trial participants were on oneof the study drugs prior to entry. Blinding isparticularly important in studies using subjec-tive measures. This may have been an evengreater factor in this trial, in which 76% of theenrollees were taking morphine prior to enroll-ment. Patients who had achieved better resultswith morphine were probably less likely toenroll. If subjects who were entered into the trialhad responded poorly to morphine relative toother patients, they could have been favorablypredisposed towards a new medication. Incom-plete cross-tolerance could also have biased theresults towards transdermal fentanyl simplybecause it was new.

This study found that, after 4 weeks of treat-ment, more patients reported good or verygood pain control for fentanyl (40%) than formorphine (19%). On the other hand, with-drawal rates favored long-acting morphine(9%) over fentanyl (16%). Functional out-comes were assessed using SF-36 and favoredfentanyl, though raw numbers were not re-ported. A subgroup analysis of the 66 enrolleeswho were naı̈ve to morphine and fentanyl atthe beginning of the study found equivalentwithdrawal rates between interventions.

How similar was the study sample to the popu-lation of interest to the clinician? As discussedabove, the subjects can best be described aspatients who have not had a good response tomorphine or another opioid in the first place.The question it appears to address is, “do pa-tients with chronic non-cancer pain accus-tomed to opioids (and who may not have had agood response to morphine or another opioid inthe first place) prefer a change to transdermalfentanyl?” The study does not address the ques-tion of greater interest to clinicians: “in unse-lected patients who have chronic pain requiringtreatment with opioids, is transdermal fentanylmore effective than long-acting morphine?”

Other aspects of the trial make its externalvalidity difficult to assess. Exclusion criteriawere not specified, and the numbers of patientsscreened and eligible for entry were not re-ported. Patients in both groups took immedi-ate-release morphine as needed to supplementtheir long-acting medication. The length of

follow-up for each drug regimen was onlyfour weeks.

The study that compared a once-daily mor-phine preparation to a twice-daily morphinepreparation21 used a randomized, double-blinded design in a population of 295 osteoar-thritis patients. Four treatment groups wereevaluated: once-daily morphine in the morn-ing, once-daily morphine in the evening, twice-daily morphine, and placebo. This study wasrated fair quality and appeared to use ade-quate blinding and randomization (EvidenceTable 1.1). Important limitations included noevaluation of the blinding, no comparison ofpersons who completed the study, high over-all withdrawal rates, and no explanation ofhow withdrawn patients were handled in dataanalysis.

This study found that once-daily morphinewas not significantly different than twice-dailymorphine for all measures of pain control (Evi-dence Table 1.1). For sleep, one of seven mea-sures of sleep quality (overall sleep quality)showed a slight but significant improvement inpatients receiving once-daily morphine in themorning (but not once-daily morphine in theevening) compared to twice-daily morphine; allother measures of sleep quality were not signifi-cantly different between once- and twice-dailymorphine. All three morphine treatmentgroups were better than placebo for most mea-sures of efficacy. Withdrawal rates were similarin all active treatment groups.

External validity of this trial was difficult toassess because the numbers of patients screenedand eligible for entry were not reported, thelength of follow-up for each drug regimen wasonly four weeks, and duration of pain and previ-ous opioid use in evaluated patients was notreported.

We found no trials directly comparing fen-tanyl or long-acting morphine to any otherlong-acting preparations.

1B. In trials comparing long-acting opioidsto other types of drugs or to placebo, is therea pattern to suggest that one long-acting opioidis more effective than another?

We identified 14 fair-quality trials (876 pa-tient enrolled) that gave indirect evidence re-garding the comparative efficacy of long-actingopioids. These trials exhibited a high degreeof heterogeneity with respect to study designs,


patient populations, interventions, and out-comes measured (Table 1). All studies wererated fair quality (see Evidence Tables 1.2 and1.3) and had at least one of the following meth-odologic problems: inadequate or poorlydescribed randomization and allocation con-cealment, lack of blinding or unclear blindingmethods, or high loss to follow-up.

Three trials evaluated long-acting codeine,22,

29,33 two long-acting dihydrocodeine,24,27 fourlong-acting morphine,26,30–32 and five long-acting oxycodone.10,23,25,28,34 The averageequipotent opioid dose received varied greatlyand in two trials was not reported.24,27 The dura-tion of follow-up ranged from 5 days to 16weeks, and a wide range of outcomes and mea-sures were employed. The most common out-comes assessed were pain intensity and rescuedrug use (Table 1). The studies used differentpain intensity measures, the most commonbeing VAS.

For most outcomes of clinical efficacy, thescales used varied too much across trials to drawmeaningful comparisons between differentlong-acting opioids. For pain intensity, for ex-ample, of five trials on oxycodone, one used aVAS,34 three others used two different (0–310,25

or 0–423) categorical scales, and one did notreport pain intensity as an outcome.28 For theoutcomes pain intensity, pain relief, and func-tional outcome, there did not appear to be apattern favoring one long-acting opioid overanother.

Functional outcomes assessment also variedwidely between studies. For sleep, the mostwidely reported functional outcome, measure-ment tools used were sleep quality (1–5 scale23

or 0–10 scale,10) nighttime rescue medicationuse,22 hours of sleep,26 average nights awakenedby pain,27 and VAS (1–100) for trouble fallingasleep and needing medication to sleep.33 Be-cause of the heterogeneity of scales used tomeasure sleep quality, meaningful comparisonsbetween long-acting opioids could not be made.Other functional outcomes were less commonlyreported and when reported were also character-ized by marked heterogeneity in measurementscales. We were unable to perform meta-analysison any subgroup of trials.

Withdrawal rates were reported in all studiesand also did not exhibit a pattern favoring onelong-acting opioid versus other long-acting opi-oids (Table 2). For long-acting oxycodone, the

withdrawal rate ranged from 4%25 to 53%.10

For long-acting morphine, the withdrawal rateranged from 0%31 to 30%.32 Similar wide rangesfor withdrawal rates were seen for the studies onlong-acting dihydrocodeine and long-acting co-deine. The wide range of withdrawal rates couldreflect differences in populations, dosing ofmedications in trials, use of a run-in period, orother factors.

The trials generally provided inadequate in-formation to accurately assess external validityor showed evidence of having highly selectedpopulations. Most trials did not report numbersof patients screened or eligible for entry andsome did not specify exclusion criteria. Whenexclusion criteria were specified, patients at riskfor drug or substance abuse were typically ex-cluded from trial participation. Numbersexcluded for meeting specific exclusion criteriawere usually not reported.

1C. Have long-acting opioids been shown tobe superior to short-acting opioids in reducingpain and improving functional outcomes whenused for treatment of adults with chronicnon-cancer pain?

A subgroup of 7 (568 patients enrolled) ofthe 14 trials reviewed for key question 1B di-rectly compared the efficacy of long-actingopioids to short-acting opioids in patients withchronic non-cancer pain (Table 3). All wererated fair quality (Evidence Table 1.2). Threestudies compared long-acting to short-acting ox-ycodone.23,25,28 One of these studies25 re-ran-domized patients who had enrolled in a previoustrial.28 Two studies evaluated long-acting di-hydrocodeine,24,27 one evaluated long-actingcodeine,22 and one evaluated long-acting mor-phine.26 Study designs, patient populations, andoutcomes assessed varied between studies (Evi-dence Table 1.2).

These trials showed no consistent trendsdemonstrating significant differences in effi-cacy between long-acting opioids as a class andshort-acting opioids (Table 3). Three studiesthat found differences in efficacy favoring long-acting morphine,26 long-acting dihydrocod-eine,27 and long-acting codeine22 had featuresthat might invalidate these results. In thetrials on long-acting morphine26 and long-acting codeine,22 the average daily doses ofopioid in the long-acting arm were higher thanthe average daily doses given in the short-acting


Tab

le2

Wit

hdra

wal

Rat

es

Ove

rall

Inad

equa

teA

uth

or,

Year

Lon

g-A

ctin

gO

pioi

dW

ith

draw

alR

ates

Wit

hdr

awal

Rat

esPe

rD

rug

Pain

Con

trol

Adv

erse

Eff

ects

Oth

er

Lon

g-ac

ting

vs.

long

-act

ing

tria

lsA

llan

2001

A:

Fen

tan

yltr

ansd

erm

al23

%A

:15

%(3

8/25

0)N

/A“1

1%”

N/A

B:

Mor

phin

eor

al(t

wic

eda

ily)

B:

9%(2

2/23

8)“4

%”

Cal

dwel

l20

02A

:M

orph

ine

(on

ceda

ilya.

m.)

38%

A:

37%

(27/

73)

917

1B

:M

orph

ine

(on

ceda

ilyp.

m.)

B:

45%

(33/

73)

1218

3C

:M

orph

ine

(tw

ice

daily

)C

:37

%(2

8/76

)8

182

D:

Plac

ebo

D:

32%

(23/

72)

145

4L

ong-

actin

gvs

.pl

aceb

oor

non-

opio

idtr

ials

Ark

inst

all

1995

Cod

ein

e28

%L

AC

odei

ne:

19%

(9/4

6)1

71

Plac

ebo:

9%(4

/46)

01

3Pe

loso

2000

Cod

ein

e36

%L

AC

odei

ne:

40%

(20/

51)

115

4Pl

aceb

o:33

%(1

7/52

)5

57

Har

ke20

01M

orph

ine

8%L

AM

orph

ine:

5%(1

/19)

NR

NR

1Pl

aceb

o:11

%(2

/19)

2H

use

2001

Mor

phin

e0%

LA

Mor

phin

e:0%

(0/1

2)N

RN

/AN

/APl

aceb

o:0%

(0/1

2)M

oulin

1996

Mor

phin

e30

%L

AM

orph

ine:

NR

NR

NR

Rot

h20

00O

xyco

don

e53

%L

AO

xyco

don

e20

mg:

42%

(19/

44)

514

0L

AO

xyco

don

e10

mg:

50%

(24/

44)

1212

0Pl

aceb

o:60

%(2

7/45

)22

23

Wat

son

1998

Oxy

codo

ne

22%

LA

Oxy

codo

ne:

12%

(6/5

0)0

51

Plac

ebo:

10%

(5/5

0)1

31

Lon

g-ac

ting

vs.

shor

t-act

ing

tria

lsC

aldw

ell

1999

Oxy

codo

ne

34%

LA

Oxy

codo

ne:

21%

(7/3

4)3

31

SAO

xyco

don

e:30

%(1

1/37

)4

52

Plac

ebo:

50%

(18/

36)

133

2H

ale

1999

Oxy

codo

ne

6%L

AO

xyco

don

e:4%

(2/4

7)0

20

SAO

xyco

don

e:2%

(1/4

7)0

11

Salz

man

1998

Oxy

codo

ne

18%

LA

Oxy

codo

ne:

20%

(6/3

0)N

R6

NR

SAO

xyco

don

e:7%

(2/2

7)0

20

(on

lyad

vers

eev

ent

wit

hdr

awal

sre

port

ed)

Hal

e19

92C

odei

ne

22%

LA

Cod

ein

e:32

%(1

7/53

)1

151

SAC

odei

ne:

12%

(6/5

1)1

50

Gos

tick

1989

Dih

ydro

code

ine

26%

NR

NR

NR

NR

Llo

yd19

92D

ihyd

roco

dein

e34

%L

AD

ihyd

roco

dein

e:47

%(2

0/43

)1

172

Dex

trop

ropo

xyph

ene

�pa

race

tam

ol:

21%

(9/4

3)2

43

Jam

ison

1998

Mor

phin

e8%

LA

Mor

phin

e�

SAO

xy.:

6%(1

/18)

NR

1N

RSA

Oxy

codo

ne:

12%

(2/1

8)0

20


Table 3Overview of Randomized Controlled Trials of Long-Acting vs. Short-Acting Opioidsa

Author, Year Pain Type Duration Patients Findings

OxycodoneCaldwell 1999 Osteoarthritis 30 days 107 LA oxycodone and SA oxycodone plus Tylenol are equally effective

for pain control and improvement of sleep.Hale 1999 Back pain 6 daysb 47 LA oxycodone and SA oxycodone are equally effective

for pain control.Salzman 1998 Back pain 10 days 57 LA oxycodone and SA oxycodone are equally effective when titrated

for pain control.Codeine

Hale 1992 Back pain 5 days 83 LA codeine plus acetaminophen are more effective for pain controlthan SA codeine plus acetaminophen, but these drugs were notgiven at therapeutically equivalent doses.

DihydrocodeineGostick 1989 Back pain 2 weeksb 61 LA dihydrocodeine and SA dihydrocodeine are equally effective

for pain control.Lloyd 1992 Osteoarthritis 2 weeks 86 LA dihydrocodeine and SA dihydrocodeine are equally effective

for pain control when compared directly.Morphine

Jamison 1998 Back pain 16 weeks 36 LA morphine plus SA oxycodone together are more effectivefor pain control than SA oxycodone, but these drugs werenot given at therapeutically equivalent doses.

aAll trials are of fair quality.bDuration per intervention of crossover trial.LA � long-acting opioid preparation; SA � short-acting opioid preparation.

group. In the other study,27 significant differ-ences in pain relief were only seen when thelong-acting dihydrocodeine group was com-pared to itself at different points in time, butno significant differences were found when thelong-acting opioid was compared directly tothe short-acting opioid. Functional outcomeswere inconsistently examined or used hetero-geneous measurement scales. Other importantoutcomes such as improved compliance or moreconsistent pain control were not examined.

A subgroup of three trials of 281 enrolledpatients evaluated roughly equivalent doses oflong- and short-acting oxycodone and appearedto be the most homogeneous of this groupof trials.23,25,28 One of these trials25 investigated are-randomized population of patients studiedin a previous trial28 but used a different inter-vention protocol. These three trials found nosignificant differences in efficacy (pain relief)between long- and short-acting oxycodone.With regard to functional outcomes, one ofthese trials23 reported improved sleep qualitywith long-acting oxycodone, but baseline sleepscores were significantly better in patients ran-domized to this intervention, which could inval-idate this finding.

2. What are the comparative incidence andnature of adverse effects (including addictionand abuse) of long-acting opioid medications

in adult patients being treated for chronic non-cancer pain?

A variety of long-acting opioids are used fortreatment of chronic non-cancer pain. Therecontinue to be concerns, however, regardingthe risk of adverse events.9 Common adverseevents associated with opioid use includenausea, cognitive dysfunction, and constipa-tion. More serious but less common adverseevents include respiratory depression, abuse,and addiction. In non-cancer pain patients,data are lacking regarding differential risks forlong-acting opioids.6

2A. In head-to-head comparisons, has one ormore long-acting opioid been shown to be asso-ciated with fewer adverse events compared toother long-acting opioids when used for treat-ment of adults with chronic non-cancer pain?

As discussed earlier, only two randomizedtrials directly compared two long-acting opi-oids. One of these trials20 compared two differ-ent long-acting opioids (transdermal fentanyland long-acting morphine) and the other21

compared once-daily versus twice-daily prepara-tions of oral morphine. Neither study assessedrates of addiction or abuse. No deaths werereported in either study.

The trial which compared transdermal fen-tanyl with long-acting oral morphine was rated


poor-quality for adverse event assessment (Evi-dence Table 2.1).20 This trial failed to ade-quately meet 6 out of the 7 predefined criteriafor adverse event assessment. This trial foundno significant differences in reported rates ofoverall or “serious” (not defined) complica-tions. Constipation was significantly lower fortransdermal fentanyl compared to long-actingmorphine (29% vs. 48%, P � 0.001) only asassessed by a bowel function questionnaire, andnot by patient-reported or investigator-ob-served symptoms. The rate of withdrawals dueto adverse event for all patients favored long-acting oral morphine (11% vs. 4%, P value notreported), but did not differ significantly inthe subgroup not previously on fentanyl ormorphine.

The trial which compared once-daily versustwice-daily preparations of oral morphine wasalso rated poor quality for adverse events (Evi-dence Table 2.1).21 This trial failed to ade-quately meet 5 out of the 7 predefined criteriafor adverse event assessment. Serious compli-cations (not defined) occurred in 6 enrolledpatients, but the rates of serious complicationswere not reported for each treatment group.This trial found a significantly higher rate ofconstipation in patients on once-daily morphinegiven in the morning (49%) versus twice-dailymorphine (29%), but a lower rate of asthenia(1% vs. 9%). The overall withdrawal rates intreated patients were not significantly differentbetween interventions and ranged from 37–45%, with withdrawal rates due to adverseevents ranging from 23–25%.

2B. In trials comparing long-acting opioidsto other types of drugs or to placebo, is therea pattern to suggest that one long-acting opioidis associated with fewer adverse events thananother?

Randomized Trials. Of the 14 trials reviewed forkey question 1B, 13 (994 patients enrolled) re-ported adverse event rates from long-acting opi-oids in patients with chronic non-cancer pain.One trial of long-acting morphine versus carba-mazepine for neuropathic pain30 was excludedbecause accurate adverse event rates could notbe abstracted from the graphs in the article.

All 13 trials were rated fair or poor qualityfor adverse event assessment and had at leastimportant methodologic flaws (Table 4; Evi-dence Tables 2.2 and 2.3). In addition, these

trials had heterogeneous study designs, inter-ventions, outcomes, and patient populations,making meaningful comparisons across stud-ies difficult (Table 1). None of these trials as-sessed rates of abuse or addiction, and allexcluded patients at risk for these complications.

These trials reported wide ranges for adverseevent rates even in studies that evaluated thesame long-acting opioid at roughly equivalentdoses. For long-acting oxycodone at mean dosesof 40 mg, for example, rates of nausea rangedfrom 15%23 to 50%28 in 5 trials (Table 4). With-drawal rates due to adverse events ranged from4%25 to 32%10 in these same studies. Given theuncertainty regarding the adverse event ratesfor individual long-acting opioids, it is not sur-prising that these trials show no discernible pat-tern of one long-acting opioid being superior toothers for any reported adverse event (Table 4).

Observational Studies. We identified 8 observa-tional studies evaluating the risk of long-actingopioids in 1190 patients with non-cancerpain.10,21,29,36–40 All were rated poor quality foradverse event assessment except one,10 whichwas rated fair (Evidence Table 2.4). For 6 ofthe 8 studies, independently assigned qualityrating scores were identical between two review-ers. For two studies, quality rating scores dif-fered by one41 or two10 points; in neither casedid this difference result in a change in overallquality rating. The single study rated fairquality10 met only 4 out of 7 predefined qualityassessment criteria. The most important areasof concern in this study were high overall loss tofollow-up (60/106) and the failure to specifyor define adverse events in advance.

Opioids assessed were long-acting codeine,29

long-acting morphine (once-daily21 or twice-daily40), transdermal fentanyl,36,39 methadone,38

and long-acting oxycodone.10 One study assessedboth methadone and long-acting morphine.37

The number of patients on long-acting opioids inthese studies ranged from 1138 to 530.39 Fivewere prospective cohort studies10,21,29,36,39 andthree were retrospective cohorts.37,38,40 No iden-tified study was population-based. Three of theprospective cohorts10,21,29 were open-label ex-tensions of clinical trials included in this review.

Results of the observational studies were notsignificantly different from those reported inclinical trials for gastrointestinal adverse events,neurological adverse events, and withdrawal


rates due to adverse events (Table 5). The studyrated fair quality,10 for example, reported a rateof 31% (32/103) of withdrawal due to ad-verse events, which fell within the range fortrials of long-acting oxycodone.

Some observational studies reported long-term outcomes and serious adverse events notreported in the trials. The largest (n � 530)study39 reported one death (0.2%, 1/530)thought related to medication, four cases ofrespiratory depression (1%), and three epi-sodes of drug abuse (0.6%). Two other studiesreported rates of abuse,37,38 but they were retro-spective studies with small samples (n � 11 and20) and no inception cohort. Four studies re-ported rates of long-term use, which could bea long-term measure of tolerability or clinicalefficacy.10,21,29,36 Rates ranged from 19% fortransdermal fentanyl36 to 54% for long-actingcodeine.29

The patients enrolled did not appear to beless selected than those in the controlled trials.In the prospective cohort studies, at least someparticipants were recruited from completedclinical trials,10,21,29,36,39 resulting in an evenmore highly selected population than the origi-nal trials. In the retrospective studies, no incep-tion cohort was identified and the populationappeared to represent a “convenience” sampleof patients for whom data was readilyavailable.37,38,40

No meaningful conclusions regarding com-parative adverse event risk of long-acting opioidscan be drawn from these observational studies.

2C. Have long-acting opioids been shown tohave fewer adverse events than short-acting opi-oids when used for treatment of adults withchronic non-cancer pain?

A subgroup of 7 of the 13 randomized trialsreviewed for key question 2B directly comparedlong-acting with short-acting opioids.22–28

In the single trial in this group rated fairquality,26 adverse events were not prespecifiedor defined and patients and investigators werenot blinded. Furthermore, patients in one armof this trial were given higher doses of opioidsthan the other. Adverse events would be ex-pected to be more common in the group receiv-ing higher doses, the result observed for mostreported adverse events (Table 4).

Across all trials, no pattern favoring eitherlong-acting or short-acting opioids was evidentfor any of the reported adverse events (Table

6). In the three most comparable studies, whichinvestigated roughly equivalent daily doses ofoxycodone in short-acting and long-actingpreparations,23,25,28 no trends favoring one for-mulation over the other were seen for the out-comes of dizziness, somnolence, vomiting, andconstipation. This was also true in the twostudies25,28 that investigated the same (re-ran-domized) population.

Withdrawals due to adverse events were re-ported in five trials (Table 4). Three favoredshort-acting opioids,22,27,28 one favored long-acting,23 and one was equivocal.25 These data arelimited by the poor quality of the trials foradverse event assessment and the fact that twoof the trials evaluated the same population.

In summary, there is no convincing evidenceto suggest superior adverse event rates withlong-acting opioids as a class compared to short-acting opioids.

3. Are there subpopulations of patients (spe-cifically by race, age, sex, or type of pain) withchronic non-cancer pain for which one long-acting opioid is more effective or associatedwith fewer adverse effects?

No clinical trials or observational studies weredesigned to compare the efficacy of long-actingopioids for different races, age groups, or sexes.There is almost no information regarding thecomparative efficacy of long-acting opioids forspecific subpopulations as characterized by race,sex, or age. Race was rarely reported in the trials;when it was reported the overwhelming majorityof patients were white. Women were well repre-sented in the trials (slightly over 50%), but differ-ential efficacy or adverse event rates accordingto sex were not evaluated. The average age ofincluded patients was 55 years, and one study34

evaluated patients with an average age of 70years. Two trials10,23 performed very limited sub-group analysis on older patients; neither trial wasa direct comparison of one long-acting opioidversus another and provide little informationregarding differential efficacy or adverse eventswithin the class of long-acting opioids.

Several specific types of chronic non-cancerpain patients were studied in some of the re-viewed trials. These categories included backpain,22,24–26,28 osteoarthritis,10,23,27,33 phantomlimb pain,31 neuropathic pain,30 and posther-petic neuralgia.34 None of these trials are direct


Tab

le4

Stud

yC

hara

cter

isti

csan

dA

dver

seE

vent

s,T

rial

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oxyc

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1999

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B:

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22)

B:

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one

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44)

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23%

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44)

A1:

32%

(14/

44)

A1:

27%

(12/

44)

A1:

20%

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4)N

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port

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20m

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0/44

)A

2:25

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1/44

)A

2:30

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3/44

)cA

2:27

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)ox

ycod

one

10m

gbi

dB

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cebo

B:

11%

(5/4

5)B

:7%

(3/4

5)B

:7%

(3/4

5)B

:4%

(2/4

5)B

:9%

(4/4

5)B

:4%

(2/4

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98A

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POO

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:50

%(1

5/30

)A

:20

%(6

/30)

A:

30%

(9/3

0)A

:27

%(8

/30)

A:

30%

(9/3

0)A

:3%

(1/3

0)A

:20

%(6

/30)

oxyc

odon

eB

:Sh

ort-a

ctin

gB

:33

%(9

/27)

B:

4%(1

/27)

B:

37%

(10/

27)

B:

37%

(10/

27)

B:

22%

(6/2

7)B

:0%

(0/2

7)B

:7%

(2/2

7)ox

ycod

one

Wat

son

1998

A:

Lon

g-ac

tin

gFA

IR(3

)N

otre

port

edN

otre

port

edN

otre

port

edN

otre

port

edN

otre

port

edN

otre

port

edN

otre

port

edox

ycod

one

B:P

lace

boL

ong-

actin

gco

dein

eA

rkin

stal

ldA

:L

ong-

acti

ng

FAIR

(3)

A:

33%

cA

:14

%A

:21

%A

:16

%A

:21

%N

otre

port

edA

:15

%(7

/46)

1995

code

ine

B:P

lace

boB

:12%

B:

3.8%

B:

10%

B:

5%B

:14%

B:

2%(1

/46)

Hal

e19

97A

:L

ong-

acti

ng

POO

R(1

)A

:31

%(1

6/52

)A

:10

%(5

/52)

A:

19%

(10/

52)

A:

10%

(5/5

2)A

:17

%(9

/52)

Not

repo

rted

A:

25%

(13/

53)

code

ine

B:S

hor

t-act

ing

B:

18%

(9/5

1)B

:2%

(1/5

1)B

:16

%(8

/51)

B:

4%(2

/51)

B:

4%(2

/51)

B:

8%(4

/51)

code

ine

(con

tinue

d)


Tab

le4

Con

tinu

ed

Con

fusi

onor

Qua

lity

Dro

wsi

nes

sor

Dif

ficu

lty

Stud

yIn

terv

enti

ons

Rat

inga

Nau

sea

Vom

itin

gC

onst

ipat

ion

Som

nol

ence

Diz

zin

ess

Con

cen

trat

ing

Wit

hdr

awal

b

Pelo

so20

00A

:L

ong-

acti

ng

FAIR

(3)

Not

repo

rted

Not

repo

rted

A:

49%

(25/

51)c

A:

39%

(20/

51)

A:

33%

(17/

51)

Not

repo

rted

A:

29%

(15/

51)

code

ine

B:P

lace

boB

:11

%(6

/52)

B:

10%

(5/5

2)B

:8%

(4/5

2)B

:8%

(4/5

2)L

ong-

actin

gdi

hydr

ocod

eine

Gos

tick

1989

A:

Lon

g-ac

tin

gPO

OR

(2)

Not

repo

rted

Not

repo

rted

A:

55%

(23/

42)e

Not

repo

rted

Not

repo

rted

Not

repo

rted

Not

repo

rted

dih

ydro

code

ine

B:S

hor

t-act

ing

B:

49%

(21/

43)

dih

ydro

code

ine

Llo

ydf

1992

A:

Lon

g-ac

tin

gPO

OR

(2)

A:

31%

(12/

39)

Not

repo

rted

A:

8%(3

/39)

A:

26%

(10/

39)

Not

repo

rted

A:

10%

(4/3

9)A

:40

%(1

7/43

)di

hyd

roco

dein

eB

:B

:10

%(4

/41)

B:

10%

(4/4

1)B

:15

%(6

/41)

Not

repo

rted

B:5

%(2

/41)

B:

9%(4

/43)

Dex

trop

ropo

xyph

ene

�pa

race

tam

olL

ong-

actin

gm

orph

ine

Hus

eg20

01A

:L

ong-

acti

ng

FAIR

(3)

A:

0.74

cmN

otre

port

edA

:0.

03cm

cA

:2.

21cm

A:

1.27

cmN

otre

port

edN

otre

port

edm

orph

ine

B:P

lace

boB

:0.

4cm

B:

0.02

cmB

:1.

33cm

B:

0.71

cmJa

mis

ond

1998

A:

Lon

g-ac

tin

gFA

IR(5

)A

:31

%N

otre

port

edA

:30

%A

:31

%A

:6%

A:

1%N

otre

port

edm

orph

ine

�sh

ort-a

ctin

gox

ycod

one

B:S

hor

t-act

ing

B:

14%

B:

18%

B:

14%

B:

19%

B:

1.4%

oxyc

odon

eM

oulin

1996

A:

Lon

g-ac

tin

gFA

IR(4

)A

:39

%(1

8/46

)cA

:39

%(1

8/46

)cA

:41

%(1

9/46

)cN

otre

port

edA

:37

%(1

7/46

)A

:9%

(4/4

6)A

:28

%h

(13/

46)

mor

phin

eB

:Ben

ztro

pin

eB

:7%

(3/4

6)B

:2%

(1/4

6)B

:4%

(2/4

6)B

:2%

(1/4

6)B

:15

%(7

/46)

B:

2%(1

/46)

a Num

ber

ofcr

iter

iaou

tof

seve

nad

equa

tely

met

.b D

ueto

adve

rse

even

ts.

c P�

0.05

for

diff

eren

cein

rate

s.d Sa

mpl

esi

zen

otcl

ear.

e Con

stip

atio

nde

fin

edas

bow

elm

ovem

ent

less

freq

uen

tly

than

ever

ytw

oda

ys.

f Res

ults

from

end

offi

rst

wee

kof

trea

tmen

tbe

caus

eof

hig

hra

teof

wit

hdr

awal

saf

ter

firs

tw

eek.

g Res

ults

repo

rted

on10

cmvi

sual

anal

ogsc

ale.

h Dos

e-lim

itin

gsi

deef

fect

s(n

otw

ith

draw

alra

te),

P�

0.00

3fo

rdi

ffer

ence

inra

tes.


Tab

le5

Stud

yC

hara

cter

isti

csan

dA

dver

seE

vent

s,O

bser

vati

onal

Stud

ies

ofL

ong-

Act

ing

Opi

oids

Con

fusi

onor

Lon

g-A

ctin

gQ

ualit

yD

row

sin

ess

Dif

ficu

lty

Lon

g-T

erm

Stud

yO

pioi

dsSt

udie

dR

atin

gaN

ause

aV

omit

ing

Con

stip

atio

nor

Som

nol

ence

Diz

zin

ess

Con

cen

trat

ing

Wit

hdr

awal

bU

se

Ark

inst

all

1995

Lon

g-ac

tin

gPO

OR

(2)

NR

NR

NR

NR

NR

NR

NR

54%

(15/

28)

code

ine

Bac

h20

01L

ong-

acti

ng

POO

R(0

)N

RN

RN

RN

RN

RN

RN

RN

Rm

orph

ine

(tw

ice-

daily

)C

aldw

ell

2002

Lon

g-ac

tin

gPO

OR

(2)

16%

6%35

%13

%9%

NR

33%

48%

mor

phin

e(2

9/18

1)(1

1/18

1)(6

3/18

1)(2

3/18

1)(1

6/18

1)(6

0/18

1)(8

6/18

1)(o

nce

-dai

ly)

Del

lem

ijn19

98T

ran

sder

mal

POO

R(2

)92

%56

%36

%58

%54

%�

20%

NR

19%

fen

tan

yl(9

/48)

Dun

bar

1996

Met

had

one

POO

R(0

)N

RN

RN

RN

RN

RN

RN

RN

RL

ong-

acti

ng

NR

NR

NR

NR

NR

NR

NR

NR

mor

phin

eG

reen

1996

Met

had

one

POO

R(0

)N

RN

RN

RN

RN

RN

RN

RN

RM

illig

an20

01T

ran

sder

mal

POO

R(1

)9%

8%N

RN

RN

RN

RN

RN

Rfe

nta

nyl

(48/

530)

(42/

530)

Rot

h20

00L

ong-

acti

ng

FAIR

(4)

24%

NR

52%

30%

NR

NR

30%

43%

oxyc

odon

e(2

5/10

6)(5

5/10

6)(3

2/10

6)(3

2/10

6)(4

6/10

6)a N

umbe

rof

crit

eria

out

ofse

ven

adeq

uate

lym

et.

b Due

toad

vers

eev

ents

.N

R�

not

repo

rted

.


Tab

le6

Com

para

tive

Res

ults

for

Adv

erse

Eve

nts,

Tri

als

ofL

ong-

Act

ing

Opi

oid

vers

usSh

ort-A

ctin

gO

pioi

d

Dro

wsi

nes

sSt

udy

Nau

sea

Vom

itin

gC

onst

ipat

ion

orSo

mn

olen

ceD

izzi

nes

sC

onfu

sion

Wit

hdr

awal

a

Lon

g-ac

ting

oxyc

odon

eC

aldw

ell

1999

Favo

rslo

ng-

acti

ng

Favo

rslo

ng-

acti

ng

Favo

rssh

ort-a

ctin

gFa

vors

lon

g-ac

tin

gFa

vors

lon

g-ac

tin

gN

otre

port

edFa

vors

lon

g-ac

tin

gH

aleb

1999

Favo

rslo

ng-

acti

ng

No

diff

eren

ceFa

vors

lon

g-ac

tin

gFa

vors

shor

t-act

ing

Favo

rssh

ort-a

ctin

gN

otre

port

edN

odi

ffer

ence

Salz

man

b19

98Fa

vors

shor

t-act

ing

Favo

rssh

ort-a

ctin

gFa

vors

lon

g-ac

tin

gFa

vors

lon

g-ac

tin

gFa

vors

shor

t-act

ing

No

diff

eren

ceFa

vors

shor

t-act

ing

Oth

erlo

ng-a

ctin

gop

ioid

sG

osti

ck19

89N

otre

port

edN

otre

port

edFa

vors

lon

g-ac

tin

gN

otre

port

edN

otre

port

edN

otre

port

edN

otre

port

edH

alec

1997

Favo

rssh

ort-a

ctin

gFa

vors

shor

t-act

ing

No

diff

eren

ceFa

vors

shor

t-act

ing

Favo

rssh

ort-a

ctin

gN

otre

port

edFa

vors

shor

t-act

ing

Llo

yd19

92Fa

vors

shor

t-act

ing

Not

repo

rted

No

diff

eren

ceFa

vors

shor

t-act

ing

Not

repo

rted

Favo

rssh

ort-a

ctin

gFa

vors

shor

t-act

ing

Jam

ison

c19

98Fa

vors

shor

t-act

ing

Not

repo

rted

Favo

rssh

ort-a

ctin

gFa

vors

shor

t-act

ing

Favo

rslo

ng-

acti

ng

No

diff

eren

ceN

otre

port

eda D

ueto

adve

rse

even

t.b St

udie

dsa

me

popu

lati

on.

c Low

erdo

seof

opio

idus

edin

shor

t-act

ing

arm

.

comparisons of one long-acting opioid with an-other. All were rated fair quality for generalmethodology and poor or fair quality for adverseevent assessment (trial quality reviewed in previ-ous sectionsof this report).Subgroupsof trials forspecific types of pain have the same problemswith heterogeneity in interventions, outcomesassessed, and findings that were encountered inexamining general efficacy and adverse events.They are further limited by the smaller numberof available trials for each type of pain. Thesetrials provide insufficient indirect evidence thatone long-acting opioid is superior to any other inany subpopulation of patients with chronic pain.

It is not possible to draw reliable conclusionsregarding comparative efficacy or adverse eventrates for any subpopulation from these data.

Summary of ResultsResults for each of the key questions are sum-

marized in Table 7. It is important to note thatwe identified no trials investigating methadoneor levorphanol in adult patients with chronicnon-cancer pain. The results refer to studiesthat investigated transdermal fentanyl and long-acting oral oxycodone, morphine, codeine,and dihydrocodeine.

In general, there was insufficient evidenceto prove that different long-acting opioids areassociated with different efficacy or adverseevent rates. Only one poor-quality trial20 di-rectly compared different long-acting opioids(transdermal fentanyl and long-acting mor-phine) and gave inconclusive results. This wasthe only trial we identified that evaluatedtransdermal fentanyl in patients with non-cancer pain. This trial may show that transder-mal fentanyl is a reasonable second choicefor patients who have inadequate pain reliefon morphine, but does not answer the generalquestion of which long-acting opioid is superiorfor the general population of patients withchronic non-cancer pain. It also did not provideconvincing evidence that transdermal fentanylis associated with less constipation than oralmorphine, as has been consistently found intrials of cancer patients.42 Another fair-qualitytrial21 that directly compared once-dailyversus twice-daily morphine also gave inconclu-sive results. Although this study found a slightimprovement in overall quality of sleep for once-daily morphine given in the morning compared


Tab

le7

Sum

mar

yof

Evi

denc

e

Key

Que

stio

ns

Lev

elof

Evi

den

ceC

oncl

usio

ns

Effic

acy

1A.

Inh

ead-

to-h

ead

com

pari

son

s,h

ason

eor

mor

elo

ng-

POO

RM

ost

lon

g-ac

tin

gop

ioid

sh

ave

not

been

com

pare

ddi

rect

lyin

clin

ical

tria

ls.

Tw

otr

ials

acti

ng

opio

idbe

ensh

own

tobe

supe

rior

toot

her

lon

g-di

rect

lyco

mpa

red

one

lon

g-ac

tin

gop

ioid

toan

oth

er.

On

epo

or-q

ualit

yst

udy

(lac

kof

acti

ng

opio

ids

inre

duci

ng

pain

and

impr

ovin

gfu

nct

ion

albl

indi

ng,

hig

hpr

opor

tion

ofpa

tien

tson

stud

ydr

ugpr

ior

toen

try,

hig

hlo

ssto

follo

w-

outc

omes

wh

enus

edfo

rtr

eatm

ent

ofad

ults

wit

hch

ron

icup

)di

rect

lyco

mpa

red

one

lon

g-ac

tin

gop

ioid

(tra

nsd

erm

alfe

nta

nyl

)to

anot

her

non

-can

cer

pain

?(m

orph

ine)

.O

ne

fair

-qua

lity

stud

yco

mpa

red

diff

eren

tlo

ng-

acti

ng

form

ulat

ion

s(o

nce

-or

twic

e-da

ily)

ofm

orph

ine,

foun

dn

osi

gnif

ican

tdi

ffer

ence

inpa

inco

ntr

olan

da

sign

ific

ant

diff

eren

cefo

ron

eof

seve

nm

easu

res

ofsl

eep

qual

ity

usin

gon

ce-d

aily

mor

phin

ein

the

a.m

.,bu

tn

otp.

m.

Th

ere

isin

suff

icie

nt

evid

ence

from

hea

d-to

-hea

dco

mpa

riso

nst

udie

sto

sugg

est

that

one

lon

g-ac

tin

gop

ioid

issu

peri

orto

anot

her

inte

rms

ofef

fica

cyin

adul

tpa

tien

tsw

ith

chro

nic

non

-can

cer

pain

.1B

.In

tria

lsco

mpa

rin

glo

ng-

acti

ng

opio

ids

toot

her

type

sPO

OR

Four

teen

tria

lsco

mpa

relo

ng-

acti

ng

opio

ids

toot

her

type

sof

drug

sor

topl

aceb

o.T

hey

are

ofdr

ugs

orto

plac

ebo,

isth

ere

apa

tter

nto

sugg

est

that

too

het

erog

eneo

usan

dof

insu

ffic

ien

tly

hig

hqu

alit

yto

com

pare

the

effi

cacy

oflo

ng-

one

lon

g-ac

tin

gop

ioid

ism

ore

effe

ctiv

eth

anan

oth

er?

acti

ng

opio

ids.

Th

ere

isin

suff

icie

nt

evid

ence

tosu

gges

tth

aton

elo

ng-

acti

ng

opio

idis

supe

rior

toan

oth

erin

term

sof

effi

cacy

inad

ult

pati

ents

wit

hch

ron

icn

on-c

ance

rpa

in.

1C.

Hav

elo

ng-

acti

ng

opio

ids

been

show

nto

besu

peri

orto

POO

RSe

ven

fair

-qua

lity

tria

lsdi

rect

lyco

mpa

reth

eef

fica

cyof

lon

g-an

dsh

ort-a

ctin

gop

ioid

sin

shor

t-act

ing

opio

ids

inre

duci

ng

pain

and

impr

ovin

gpa

tien

tsw

ith

chro

nic

non

-can

cer

pain

.T

hes

etr

ials

wer

eh

igh

lyh

eter

ogen

eous

,in

term

sfu

nct

ion

alou

tcom

esw

hen

used

for

trea

tmen

tin

adul

tsw

ith

ofst

udy

desi

gn,

pati

ent

popu

lati

ons,

inte

rven

tion

s,an

dou

tcom

esas

sess

ed.

chro

nic

non

-can

cer

pain

?T

her

eis

insu

ffic

ien

tev

iden

ceto

sugg

est

supe

rior

effi

cacy

oflo

ng-

acti

ng

opio

ids

asa

clas

sco

mpa

red

tosh

ort-a

ctin

gop

ioid

sin

adul

tsw

ith

chro

nic

non

-can

cer

pain

.T

hre

eof

the

tria

lsco

mpa

relo

ng-

acti

ng

oxyc

odon

eto

shor

t-act

ing

oxyc

odon

ean

dw

ere

mor

eh

omog

eneo

us.

Non

efo

und

diff

eren

ces

incl

inic

alef

fica

cy.

Th

ere

isfa

irev

iden

ceto

sugg

est

that

lon

g-ac

tin

gox

ycod

one

and

shor

t-act

ing

oyxc

odon

ear

eeq

ually

effe

ctiv

efo

rpa

inco

ntr

olin

adul

tpa

tien

tsw

ith

chro

nic

non

-can

cer

pain

.A

dver

seEv

ents

2A.

Inh

ead-

to-h

ead

com

pari

son

s,h

ason

eor

mor

elo

ng-

POO

RM

ost

lon

g-ac

tin

gop

ioid

sh

ave

not

been

com

pare

ddi

rect

lyin

clin

ical

tria

ls.

On

epo

or-

acti

ng

opio

idbe

ensh

own

tobe

asso

ciat

edw

ith

few

erqu

alit

ytr

ial

(see

abov

e)di

rect

lyco

mpa

res

one

lon

g-ac

tin

gop

ioid

wit

han

oth

eran

don

ead

vers

eev

ents

com

pare

dto

oth

erlo

ng-

acti

ng

opio

ids

wh

enfa

ir-q

ualit

ytr

ial

(see

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to twice-daily morphine, it also found signifi-cantly more constipation in the once-daily mor-phine group (though less asthenia). Othermeasures of sleep quality and pain control werenot significantly different. Studies that providedindirect data were too heterogeneous in terms ofstudy design, patient populations, interventions,assessed outcomes, and results to make accuratejudgments regarding comparative efficacy or ad-verse event rates. The comparative efficacyand adverse event rates of different long-actingopioids in adult patients with chronic non-cancer pain remains uncertain. In general, insuf-ficient data was provided in the included trialsto accurately assess external validity.

There was also insufficient evidence from asubgroup of seven trials to determine whetherlong-acting opioids as a class are more effectiveor associated with fewer adverse events thanshort-acting opioids. Three trials investigatinglong-acting oxycodone versus short-acting oxy-codone23,25,28 were more homogeneous andprovided fair evidence that long-acting andshort-acting oxycodone are equally effective forpain control. It is not clear whether recentmedia attention and case reports of abuse, ad-diction, and overdose (including respiratory de-pression) from long-acting opioids represent atrue increased risk or are proportionate to pre-scribing pattern changes.1 There also may beother reasons (such as convenience, improvedcompliance, or more consistent pain relief) forprescribing long-acting opioids, but these out-comes were not assessed in the reviewed trials.

Essentially no good-quality data are avail-able to assess comparative efficacy and adverseevent risks in subpopulations of patients withchronic non-cancer pain.

DiscussionThe current available literature does not pro-

vide enough evidence to guide the prescribingphysician in choosing an initial long-actingopioid medication for patients with chronic non-cancer pain. The lack of high-quality evidencecomparing long-acting opioids to one anotherand to short-acting opioids in patients withchronic non-cancer pain is concerning given thewide use of this class of medication in this popu-lation. Data are inadequate to determinewhether long-acting opioid preparations, eithercompared to each other or to short-acting opi-oids, have different efficacy and safety profiles.

Given the ever-rising costs of medications, itis likely that pressure will continue to increaseto watch the bottom line. Without good qualityevidence of comparative efficacy and safety,payers may be compelled to rely on cost as theonly method of differentiating between medica-tions in this drug class, or extrapolate fromstudies performed in other populations (e.g.,cancer pain patients) that may not be applicableto the population in question.

Ideal studies to investigate comparative effi-cacy and safety would perform head-to-headcomparisons of equianalgesic doses of long-acting opioids to other long-acting or short-acting opioids, be adequately blinded, use a pre-defined and systematic method for identifyingadverse events, be of longer duration, and ac-count for prior opioid use of enrollees. Large,population-based observational studies wouldhelp determine whether rare but serious adverseevent rates (such as respiratory depression) dif-fered between long-acting opioids. Particular at-tention to the risks of abuse and addiction wouldalso be best obtained from high-quality cohortstudies, as trials have typically excluded patientsat high risk for these complications. Outcomesshould be standardized or measured using a vari-ety of visual analogue scales, categorical scales,and common multiquestion assessments, so thatresults can be meaningfully compared acrossstudies. Another area that deserves careful studyis the efficacy of opioid rotation in this group ofpatients. We hope this report helps to highlightremaining gaps in our understanding of this im-portant class of medication and that studies tofill these gaps will be supported and undertaken.

AcknowledgmentsThe authors wish to acknowledge the Oregon

Department of Human Resources for its fund-ing support. They also wish to acknowledge theadministrative support provided by KathrynPyle Krages, AMLS, MA, Susan Wingenfeld,Susan Carson, MPH, and Patty Davies, MS.Additional information regarding Oregon’sPractitioner-Managed Prescription Drug Planis available at http://www.ohpr.state.or.us.

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Appendix ASearch Strategy

1 exp analgesics, opioid/or “opioid analgesics”.mp.2 exp narcotics/or “narcotics”.mp.3 1 or 24 (intractable pain or severe pain or chronic pain).mp.5 3 and 46 limit 5 to human7 limit 6 to english language8 6 not 79 limit 8 to abstracts

10 7 or 9

Appendix BMethods for Drug Class Reviews for Oregon

Health Plan Practitioner-Managed PrescriptionDrug Plan Oregon Health & Science University Evi-dence-Based Practice Center December 14, 2001

Available at http://www.oregonrx.org/OrgrxPDF/Opioid%20Review.htm or from the authors.


Appendix CQuality Abstraction Tool for Adverse Events of Opioids

Author Study

Year published

Citation

Setting (country, single or multicenter, specialty or primary care clinic)

Type of study (RCT, crossover, population-based, retrospective cohort, prospective cohort)

INTERNAL VALIDITY

Selection:1: Study states “all patients” or “consecutive series” during specified time period (observational study) or describes andaccounts for all patients deemed eligible (clinical trial) and has explicit inclusion and exclusion criteria applied to all eligiblepatients (all study types)0: Selection not clear, biased selection, inclusion and exclusion criteria not specified, or unable to determine proportion ofpatients eligible for trial who withdrew or were not entered

Loss to follow-up:1: Low overall and differential loss to follow-up (�15% of study population or �25% difference between groups), able tocompute adverse effects according to intention-to-treat if low loss to follow-up0: High overall or differential loss to follow-up (>15% overall or �25% difference between groups), or unable to calculateintention-to-treat if low loss to follow-up

Adverse events pre-specified and pre-defined:1: Study reports definitions used for assessed adverse events in an explicit, reproducible fashion0: Study does not meet above criteria

Ascertainment techniques adequately described:1: Study reports methods used to ascertain complications, including who ascertained, timing, and methods used0: Study does not meet above criteria

Non-biased and accurate ascertainment of adverse events:1: Patients and assessors blinded to intervention and ascertainment techniques go beyond patient self-report alone0: Study does not meet above criteria

Statistical analysis of potential confounders:1: Study examines more than 2 relevant confounders/risk factors using standard acceptable statistical techniques0: Study does not meet above criteria

Adequate duration of follow-up:1: Study reports duration of follow-up and duration at least 7 days0: Study does not meet above criteria

Internal validity score (0-7)

EXTERNAL VALIDITY

Adequate description of study population:1: Study reports 2 or more demographic characteristic and both basic clinical characteristics of pain syndrome and averageduration of pain0: Study does not meet above criteria

Does study report numbers screened and eligible (trial) or inception cohort (observational study)?

Are exclusion criteria specified and numbers excluded for each criteria reported?

Who is the funding source?

Are authors employed by the funding source?

Are data held by the funding source?

Are patients in the study on opioids prior to study entry?


Appendix DClinical Trials Search Results

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