Opioids for Chronic Low Back Pain
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The primary objective of this review will be to determine whether opioids are effective in improving pain and/or function in individuals with chronic LBP.
Secondary objectives will be to determine the effectiveness of opioids in:
1. patients with chronic LBP with or without prior spinal surgery
2. patients with LBP with or without radicular symptoms (patients with symptoms radiating into the buttock or leg irrespective of radiological or electrophysiological evidence).
Background
Low‐back pain (LBP), though rarely due to a life‐threatening disorder, is a significant cause of distress and a major cause of pain, disability, and social cost in low‐, middle‐ and high‐ income (Western) nations (Volinn 1997). Estimates suggest that 70% to 80% of people will experience at least one episode of back pain (acute) during their lifetime. Although the majority (60% to 70%) of these individuals recover by six weeks, and 80% to 90% improve by 12 weeks (Shekelle 1995), a significant minority continue to report symptoms over many months. For example, in one study, one third of patients with LBP (unspecified etiology) continued to be symptomatic at 12 months follow‐up (Thomas 1999). Moreover, a substantial proportion of people with back pain will have recurrences even after an initial resolution of symptoms (Von Korff 1996). Those individuals with persistent LBP not only experience personal distress, but may also sustain significant disabilities as a result of their symptoms. According to an older study (Spitzer 1987), after 12 weeks, less than 50% of individuals with continuing LBP will return to work by six months. An absence of two years from employment has been associated with almost no chance of returning to work. In contrast, more recent work (Atlas 2000) has identified the return‐to‐work rates of individuals diagnosed with sciatica. At the four‐year mark, depending on whether the individual was in receipt of worker's compensation or not, the return to work rate was either 80% or 87%, respectively .
The majority of treatments for chronic LBP are directed towards symptom management and functional improvement. Patients may receive a variety of treatment regimes, in isolation or in combination, including modalities for pain management (e.g. Transcutaneous electrical nerve stimulation (TENS), massage therapy, medications, work hardening) or more invasive techniques, such as, injection therapy (epidurals, facet blocks and trigger points) directed specifically at potential anatomic causes for chronic LPB. Only a small proportion of persons with chronic LBP will undergo back surgery. Despite general acceptance of lumbar discectomy, with or without decompression, and/or lumbar fusion, the actual success rates for symptomatic and functional improvement have been variable, with surgical 'failure' rates between 10% and 40% (Fritsch 1996; Ostelo 2003). These individuals often return to the pool of patients with chronic LBP and have a poor chance of recovery regardless of future treatment. Medications play a significant role in the management of chronic LBP and generally fall into three broad categories: non‐steroidal anti‐inflammatory drugs (NSAIDs), sedatives/relaxants, and opioids. All types of drugs may be prescribed for analgesia independently, or in combination.
A controversial issue in the management of chronic non‐cancer pain (NCP) in general, and chronic LBP in particular, is the administration of opioids. The use of opioids in pain management for chronic NCP continues to escalate. Market data have indicated that since 2000, long acting and short acting opioids have experienced a 26.5% and 39% compound annual growth rate, respectively (ZARS 2003). Despite increased use, the medical community continues to disagree about the use of opioids in chronic NCP. While many clinicians believe that these medications offer a valuable tool in the management of chronic NCP, there is still a large group of practitioners who remain hesitant, or even opposed, to the use of opioids in managing chronic NCP. A recent survey, asking 100 Canadian physicians about their attitudes towards opioid use for chronic pain, confirmed that 35% of general practitioners and 23% of palliative care physicians would never use opioids for the management of severe chronic NCP (Morley‐Foster 2003). Clinicians reluctant to use opioids in chronic NCP perceive that the risk of addiction, somnolence with resulting poor function, and general ineffectiveness of opioids far out weigh any benefit that may exist. A recent study (Breckenridge 2003) showed that rather than their underlying pathology, characteristics such as age, depression, personality disorder, and substance abuse distinguished patients with chronic LBP who were on opioids from those who were receiving non‐opioid treatments. Studies such as these only add to the confusion, creating further debate about indications and actual benefits of treating chronic NCP with opioids. This study will attempt to review the current evidence for the effectiveness of opioids in chronic NCP, specifically chronic LBP.
Objectives
The primary objective of this review will be to determine whether opioids are effective in improving pain and/or function in individuals with chronic LBP.
Secondary objectives will be to determine the effectiveness of opioids in:
1. patients with chronic LBP with or without prior spinal surgery
2. patients with LBP with or without radicular symptoms (patients with symptoms radiating into the buttock or leg irrespective of radiological or electrophysiological evidence).
Methods
Criteria for considering studies for this review
Types of studies
The review will include randomized controlled trials (RCTs), quasi‐randomized trials (a CCT that uses methods of allocation that are subject to bias in assignment, such as, odd‐even numbers on day of week, patient record, or social security number), and non‐randomized controlled clinical trials (CCT). There will be no restrictions on language of publication. For studies not published in English, the authors will ask the Back Review Group coordinator for assistance in locating suitable translators for data extraction and methodological assessment.
Types of participants
Inclusion criteria
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Male and female individuals
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18 years or older
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Persistent pain in the low back that has lasted for at least 12 weeks, with or without radiating symptoms to the legs, with or without prior low‐back surgery
Low‐ back pain will be defined as pain occurring below the lower ribs and above the gluteal folds, including the buttocks.
Failed back surgery syndrome will be defined as patients who require treatment for persistent pain that has lasted longer than six months from the date of surgical intervention, or pain that began prior to one year from the date of intervention, after the individual had achieved symptomatic relief.
Exclusion criteria
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Patients with cancer, infections, inflammatory arthritic conditions and compression fractures
Types of interventions
We will include trials that examine the use of any opioid prescribed in an outpatient setting, for a period of one month or longer. Trials may examine opioids given by oral, transdermal, mucosal (nasal or rectal), or intramuscular routes. Opioids may be administered alone or in combination with other interventions: pharmacological therapy (e.g., anti‐inflammatories, anti‐depressants, sedatives), physical modalities (e.g., TENS, chiropractic), exercise, or alternative pain management techniques (e.g., acupuncture).
We will exclude trials that examine opioids given by an intravenous route, including implantable pumps, due to the invasive nature of the therapy and its limited clinical relevance in the outpatient setting.
We will review the following comparisons:
1. Opioids compared to placebo;
2. Opioids compared to no treatment;
3. Opioids compared to non‐pharmacological treatments;
3. Opioids compared to other pharmacological agents, alone or in combination (e.g., NSAIDs, muscle relaxants, anti‐depressants);
4. Opioids given in combination with other pharmacological agents (e.g., NSAIDs, muscle relaxants, anti‐depressants) and/or non‐pharmacological treatments compared to other pharmacological agents and/or non‐pharmacological, alone or in combination.
Types of outcome measures
This review will focus explicitly on four primary outcome measures for efficacy: pain ratings (e.g., Verbal rating scale, Visual analog scale), function (e.g., Oswestry, Roland‐Morris), global functioning (patient satisfaction, quality of life improvements), impairment and disability (activities of daily living (ADL), return to work,). It will also focus on treatment side effects.
Other factors such as healthcare usage, non‐opioid medication consumption and addiction prevalence or change in venue of treatment will be considered secondary outcomes.
Outcome measures will be grouped according to the timing of post‐randomization follow‐up: very short‐term (less than one month), short‐term (between one and three months), intermediate (between three and six months) and long‐term (longer than six months).
Search methods for identification of studies
Relevant trials meeting the inclusion criteria will be identified by:
1. Electronic searches of the following databases.
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Cochrane Central Register of Controlled Trials (current issue at time of search)
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MEDLINE (1966 to present)
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EMBASE (1980 to present)
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PsychINFO (beginning of database to present)
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CINAHL (beginning of database to present)
2. Examination of references provided in relevant systematic reviews and identified trials
3. Citation tracking of identified relevant trials
4. Contact with experts in the field
Electronic searches will be performed with the assistance of an experienced librarian, using the sensitive searches recommended by the Updated Method Guidelines for Systematic Reviews in the Cochrane Collaboration Back Review Group (van Tulder 2003).
The search strategy for MEDLINE can be found in Additional Table 2 (Table 1). The search strategy for EMBASE can be found in Additional Table 3 (Table 2). These search strategies will be adapted as indicated to search the other databases.
| 001 randomized controlled trial.pt. |
| 1 exp Clinical Trial/ |
Data collection and analysis
Methods used in this review will follow the Updated Method Guidelines for Systematic Reviews in the Cochrane Collaboration Back Review Group (van Tulder 2003).
Study Selection
Two authors will independently screen the titles, abstracts, and keywords of trials identified by the search strategies to determine if the reference meets the inclusion criteria. The full text of the trials that appear to meet the criteria, or for which their inclusion is uncertain, will be obtained and reviewed for further clarification. The authors will meet to reach consensus. In the event consensus cannot be reached, a third author will be asked to complete the activity and resolve the disagreement.
Methodological Quality
Two authors will independently evaluate the methodological quality of the selected articles, based on the criteria described in the Back Review Group's updated methods guidelines (van Tulder 2003). Each criterion will be scored as "positive", "negative" or "unclear". A total score will be computed by counting the number of positive scores. High quality will be defined as fulfilling six or more of the internal validity criteria (possible total score of 11). The description of this evaluation is outlined in Table 01 (Table 3). If information is absent for evaluation of the methodological criteria, the authors of the study will be contacted to provide additional information. The authors will meet to reach consensus. In the event consensus cannot be reached, a third author will be asked to complete the activity and resolve the disagreement.
Since several of the authors are considered experts in the field, they will possibly be familiar with the articles abstracted. Thus, it will be impractical to blind the authors to the author, institution or journal.
| Validity Criteria | Operationalization |
| 1. Was the method of randomization adequate? | 1. A random (unpredictable) assignment sequence. Examples of adequate methods are computer generated random number tables and use of sealed or opaque envelopes. Methods of allocation using date of birth, date of admission, hospital numbers, or alternation should not be regarded as appropriate. |
| 2. Was the treatment allocation concealed? | 2. Assignment generated by an independent person not responsible for determining the eligibility of the patients. This person has no information about the persons included in the trial and has no influence on the assignment sequence or on the decision about eligibility of the patient. |
| 3. Were the groups similar at baseline regarding the most important prognostic indicators? | 3. In order to receive a 'yes', groups have to be similar at baseline regarding demographic factors, duration and severity of complaints, percentage of patients with neurological symptoms and value of main outcome measurement(s). |
| 4. Was the patient blinded to the intervention? | 4. Blinding should be adequate. The reviewer determines if enough information about blinding is given in order to score a 'yes'. |
| 5. Was the care provider blinded to the intervention? | 5. Blinding should be adequate. The reviewer determines if enough information about blinding is given in order to score a 'yes'. |
| 6. Was the outcome assessor blinded to the intervention? | 6. Blinding should be adequate. The reviewer determines if enough information about blinding is given in order to score a 'yes'. |
| 7. Were co‐interventions avoided or similar? | 7. Co‐interventions should either be avoided in the trial design or comparable between the index and control groups. |
| 8. Was the drop‐out rate during the intervention period described and acceptable? | 8. The number of participants who were included in the study, but did not complete the observation period or were not included in the analysis, must be described and the reasons given. If the percentage of withdrawals and drop‐outs does not exceed 20% for short‐term follow‐up and 30% for long‐term follow‐up and does not lead to substantial bias, a 'yes; is scored. |
| 9. Was the compliance rate (in each group) acceptable? | 9. The reviewer determines if the compliance to the interventions is acceptable, based on the reported intensity, duration, number and frequency of sessions for both the index intervention and control intervention(s). |
| 10. Was the timing of the outcome assessment in both groups comparable? | 10. Timing of outcome assessment should be identical for all intervention groups and for all important outcome assessments. |
| 11. Did the analysis include an intention‐to‐treat analysis? | 11. All randomized patients are reported/analyzed in the same group as allocated by randomization for the most important moments of effect measurement (minus missing values) regardless of non‐compliance and co‐interventions |
Data Extraction
Two authors will independently extract data, using the standardized forms developed by the Back Review Group, on characteristics of the participants, intervention group, clinical setting, method of recruitment, interventions, primary and secondary outcomes, opioid abuse, opioid addiction, side effects, country of study and sponsorship of study. If data are not available in a format that is appropriate for extracting, the authors of the study will be contacted for further clarification. If not satisfactory, the study data will not be included in the meta‐analysis, should there be sufficient data available from other relevant studies to complete one. The authors will meet to reach consensus. In the event consensus cannot be reached, a third author will be asked to complete the activity and resolve the disagreement. Authors will not be blinded.
Data Analysis
The choice between qualitative and quantitative (meta‐analysis) pooling will be based first on clinical homogeneity. Clinically homogeneous studies will be defined as those with similar populations, interventions, and outcomes measured at the same follow‐up point. Studies with sufficient data, judged clinically homogeneous will be pooled using RevMan 4.2 software. Tests for statistical heterogeneity will be performed. When studies are statistically heterogeneous, a random effects model will be used, otherwise a fixed effect model will be used. All estimates will involve a 95% confidence interval (95%CI).
We will perform the following subgroup analyses will be performed if sufficient data are available:
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Route of opioid delivery (oral, intramuscular and transdermal);
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Type of opioid (morphine, codeine, oxycodone, hydromorphone, fentanyl) ‐ adjustments will be made for dosing equivalency;
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Duration of treatment (shorter than 12 months and 12 months or longer);
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Chronic LBP‐non‐surgical v. prior spine surgery (failed back surgery syndrome);
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Chronic LBP with and without radiating symptoms;
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Pharmaceutical sponsored studies compared to non‐sponsored trials.
A qualitative analysis will be completed if the studies are found to be clinically heterogeneous, or if the relevant data to complete statistical pooling is unavailable. A rating system, based on the levels of evidence, will be used to summarize the strength of scientific evidence of the effects of the treatment. The rating system will be based on both the quality and outcome of the studies (van Tulder 2003):
I. Strong evidence ‐ consistent evidence in multiple high quality RCTs.
II. Moderate evidence ‐ consistent findings in multiple low quality RCTs and/or CC Ts and/or one high quality RCT
III. Limited ‐ one low quality RCT or CCT
IV. Conflicting evidence ‐ inconsistent findings in multiple RCTs and/or CCTs
V. No evidence ‐ no RCTs or CCTs
Clinical Relevance
Two authors will independently assess the clinical relevance of the results for the completed systematic review, meeting to reach consensus. As before, a third author will be consulted in situations where consensus cannot be reached. The following questions will be used to determine the value of this systematic review to clinical practice.
1. Are the patients described in detail, so that you can decide whether they are comparable to those you see in your practice?
2. Are the interventions and treatment settings described well enough so that you can provide the same for your patients?
3. Were all clinically relevant outcomes measured and reported?
4. Is the size of the effect clinically important?
5. Are the likely treatment benefits worth the potential harms?
Answers to questions 1, 2 and 3 will be grouped by type of outpatient setting. These settings may include primary care office, hospital based pain clinic or multidisciplinary pain clinic. Responses to questions 4 and 5 will be determined from the completed review and will be dependent on the ability to statistically pool outcomes.
| 001 randomized controlled trial.pt. |
| 1 exp Clinical Trial/ |
| Validity Criteria | Operationalization |
| 1. Was the method of randomization adequate? | 1. A random (unpredictable) assignment sequence. Examples of adequate methods are computer generated random number tables and use of sealed or opaque envelopes. Methods of allocation using date of birth, date of admission, hospital numbers, or alternation should not be regarded as appropriate. |
| 2. Was the treatment allocation concealed? | 2. Assignment generated by an independent person not responsible for determining the eligibility of the patients. This person has no information about the persons included in the trial and has no influence on the assignment sequence or on the decision about eligibility of the patient. |
| 3. Were the groups similar at baseline regarding the most important prognostic indicators? | 3. In order to receive a 'yes', groups have to be similar at baseline regarding demographic factors, duration and severity of complaints, percentage of patients with neurological symptoms and value of main outcome measurement(s). |
| 4. Was the patient blinded to the intervention? | 4. Blinding should be adequate. The reviewer determines if enough information about blinding is given in order to score a 'yes'. |
| 5. Was the care provider blinded to the intervention? | 5. Blinding should be adequate. The reviewer determines if enough information about blinding is given in order to score a 'yes'. |
| 6. Was the outcome assessor blinded to the intervention? | 6. Blinding should be adequate. The reviewer determines if enough information about blinding is given in order to score a 'yes'. |
| 7. Were co‐interventions avoided or similar? | 7. Co‐interventions should either be avoided in the trial design or comparable between the index and control groups. |
| 8. Was the drop‐out rate during the intervention period described and acceptable? | 8. The number of participants who were included in the study, but did not complete the observation period or were not included in the analysis, must be described and the reasons given. If the percentage of withdrawals and drop‐outs does not exceed 20% for short‐term follow‐up and 30% for long‐term follow‐up and does not lead to substantial bias, a 'yes; is scored. |
| 9. Was the compliance rate (in each group) acceptable? | 9. The reviewer determines if the compliance to the interventions is acceptable, based on the reported intensity, duration, number and frequency of sessions for both the index intervention and control intervention(s). |
| 10. Was the timing of the outcome assessment in both groups comparable? | 10. Timing of outcome assessment should be identical for all intervention groups and for all important outcome assessments. |
| 11. Did the analysis include an intention‐to‐treat analysis? | 11. All randomized patients are reported/analyzed in the same group as allocated by randomization for the most important moments of effect measurement (minus missing values) regardless of non‐compliance and co‐interventions |
