Single dose intra‐articular morphine for pain control after knee arthroscopy
Abstract
Background
Knee arthroscopy is a common procedure and is associated with postoperative pain. Intra‐articular (IA) injection of morphine for pain control has been widely studied, but its analgesic effect after knee arthroscopy is uncertain.
Objectives
To evaluate the relative effects on pain relief and adverse events of IA morphine given for pain control after knee arthroscopy compared with placebo, other analgesics (local anaesthetics, non‐steroidal anti‐inflammatory drugs (NSAIDs), other opioids) and other routes of morphine administration.
Search methods
We searched CENTRAL (The Cochrane Library Issue 4, 2015), MEDLINE via Ovid (January 1966 to May 2015), EMBASE via Ovid (January 1988 to May 2015), and the reference lists of included articles. We also searched the metaRegister of controlled trials, clinicaltrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform for ongoing trials.
Selection criteria
We identified all the randomised, double‐blind controlled trials that compared single dose IA morphine with other interventions for the treatment of postoperative pain after knee arthroscopy. We excluded studies with fewer than 10 participants in each group, using spinal or epidural anaesthesia, or assessing the analgesic effect of IA morphine on chronic pain.
Data collection and analysis
Two authors independently assessed the quality of each trial and extracted information on pain intensity, supplementary analgesics consumption and adverse events. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created 'Summary of findings' tables.
Main results
We included 28 small, low quality studies (29 reports) involving 2564 participants. Of 20 studies (21 reports) comparing morphine with placebo, nine studies with adequate data were included in the meta‐analysis. Overall, the risk of bias was unclear. Overall, the quality of the evidence assessed using GRADE was low to very low, downgraded primarily due to risk of bias, small study size, and imprecision.
No statistical difference was found between 1 mg IA morphine and placebo in pain intensity (visual analogue scale (VAS)) at early phase (zero to two hours) (mean difference (MD) ‐0.50, 95% CI ‐1.15 to 0.14; participants = 297; studies = 7; low quality evidence), medium phase (two to six hours) (MD ‐0.47, 95% CI ‐1.09 to 0.14; participants = 297; studies = 7; low quality evidence) and late phase (six to 30 hours) (MD ‐0.88, 95% CI ‐1.81 to 0.04; participants = 297; studies = 7; low quality evidence). No significant difference was found between 1 mg and 2 mg morphine for pain intensity at early phase (MD ‐0.56, 95% CI ‐1.93 to 0.81; participants = 105; studies = 2; low quality evidence), while 4 mg/5 mg morphine provided better analgesia than 1 mg morphine at late phase (MD 0.67, 95% CI 0.08 to 1.25; participants = 97; studies = 3; low quality evidence). IA morphine was not better than local anaesthetic agents at early phase (MD 1.43, 95% CI 0.49 to 2.37; participants = 248; studies = 5; low quality evidence), NSAIDs at early phase (MD 0.95, 95% CI ‐0.95 to 2.85; participants = 80; studies = 2; very low quality evidence), sufentanil, fentanyl or pethidine for pain intensity. IA morphine was similar to intramuscular (IM) morphine for pain intensity at early phase (MD 0.21, 95% CI ‐0.48 to 0.90; participants = 72; studies = 2; very low quality evidence).
Meta‐analysis indicated that there was no difference between IA morphine and placebo or bupivacaine in time to first analgesic request. Eleven out of 20 studies comparing morphine with placebo reported adverse events and no statistical difference was obtained regarding the incidence of adverse events (risk ratio (RR) 1.09, 95% CI 0.51 to 2.36; participants = 314; studies = 8; low quality evidence). Seven of 28 studies reported participants' withdrawal. There were not enough data for withdrawals to be able to perform meta‐analysis.
Authors' conclusions
We have not found high quality evidence that 1 mg IA morphine is better than placebo at reducing pain intensity at early, medium or late phases. No statistical difference was reported between IA morphine and placebo regarding the incidence of adverse events. The relative effects of 1 mg morphine when compared with IA bupivacaine, NSAIDs, sufentanil, fentanyl and pethidine are uncertain. The quality of the evidence is limited by high risk of bias and small size of the included studies, which might bias the results. More high quality studies are needed to get more conclusive results.
PICOs
Plain language summary
Morphine injections for pain relief after knee arthroscopy
Background
Knee arthroscopy is a surgical procedure on the knee. The surgery is minimally invasive, which means that only a small cut (incision) is needed. An examination, and sometimes treatment, of damage is performed using an arthroscope, which is inserted into the joint through the small incision. Knee arthroscopy is used to assess or treat many orthopaedic (musculoskeletal) conditions, and patients may have pain after surgery. Morphine injected directly into the knee (intra‐articular morphine) to relieve pain has been widely studied, but we do not know how well it works.
Key results and quality of the evidence
In May 2015, this review identified 28 small, low quality studies involving 2564 participants looking at intra‐articular morphine for pain relief after knee arthroscopy. From 9/20 studies we did not find evidence that intra‐articular morphine given at a dose of 1 mg was better than placebo for pain relief. From the limited evidence available we were unable to determine how intra‐articular morphine compared with morphine injected into the muscle (intra‐muscular morphine). There was also low quality evidence for the effects of 1 mg intra‐articular morphine compared with intra‐articular bupivacaine, non‐steroidal anti‐inflammatory drugs (NSAIDs), sufentanil, fentanyl and pethidine, so we were unsure which worked best. We were unable to determine how similar the rates of side effects such as nausea and vomiting were between intra‐articular morphine and placebo. Overall, the quality of the evidence was low.
Future research should focus on finding effective analgesics for knee arthroscopy.
Authors' conclusions
Summary of findings
| Morphine compared with placebo for pain control after knee arthroscopy | ||||||
| Patient or population: patients undergoing knee arthroscopy Comparison: placebo (saline) administered via the knee joint | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo | Morphine | |||||
| Pain intensity VAS score | The mean pain score in placebo groups ranged from | The mean pain score in the 1 mg morphine groups was 0.5 cm lower | 297 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score | The mean pain score in placebo groups ranged from | The mean pain score in the 1 mg morphine groups was 0.47 cm lower | 297 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score | The mean pain score in placebo groups ranged from | The mean pain score in the 1 mg morphine groups was 0.88 cm lower | 297 | ⊕⊕⊝⊝ | ||
| Analgesia duration | See comment | See comment | Not estimable | 124 | ⊕⊕⊝⊝ | The data were not pooled. |
| Adverse events | Study population | RR 1.09 | 314 | ⊕⊕⊝⊝ | ||
| 103 per 1000 | 97 per 1000 | |||||
| Moderate | ||||||
| 80 per 1000 | 76 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded one level due to risk of bias: the included studies had small group size and were of low quality. Some studies did not describe randomisation and allocation concealment processes adequately. 2 Downgraded one level due to publication bias: we could not extract usable data for 11 out of 20 studies comparing morphine with placebo. Some studies presented data as figures and not enough data can be used. 3 Downgraded one level due to risk of bias: one of the included studies (Kanbak 1997) was of low quality. 4 Downgraded one level due to publication bias: only three out of 20 studies presented data of analgesic duration. 5 Downgraded one level due to risk of bias: two out of eight studies were of low quality. 6 Downgraded one level due to publication bias: the reported adverse events were not the same. Some only reported the overall incidence of adverse events and some reported a series of adverse events including nausea and vomiting. | ||||||
| Morphine compared with bupivacaine for pain control after knee arthroscopy | ||||||
| Patient or population: patients undergoing knee arthroscopy Comparison: bupivacaine administered via the knee joint | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Bupivacaine | Morphine | |||||
| Pain intensity VAS score | The mean pain score in bupivacaine groups ranged from | The mean pain score in the morphine groups was | 248 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score | The mean pain score in bupivacaine groups ranged from | The mean pain score in the morphine groups was | 330 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score | The mean pain score in bupivacaine groups ranged from | The mean pain score in the morphine groups was | 270 | ⊕⊕⊝⊝ | ||
| Analgesia duration | See comment | See comment | Not estimable | 162 | ⊕⊕⊕⊝ | The data were not pooled. |
| Adverse events | Study population | RR 0.68 (0.09 to 5.17) | 210 | ⊕⊕⊕⊝ | ||
| 76 per 1000 | 49 per 1000 | |||||
| Moderate | ||||||
| 40 per 1000 | 26 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded one level due to risk of bias: the included studies have small group size and are of low quality. Some studies did not describe randomisation and allocation concealment processes adequately. 2 Downgraded one level due to publication bias: six out of 12 studies have exact data for meta‐analysis and others cannot be included in meta‐analysis due to incomplete reporting of outcomes. 3 Downgraded one level due to publication bias: seven out of 12 studies have exact data for meta‐analysis and others cannot be included in meta‐analysis due to incomplete reporting of outcomes. 4 Downgraded one level due to publication bias: five out of 12 studies have exact data for meta‐analysis and others cannot be included in meta‐analysis due to incomplete reporting of outcomes. 5 Downgraded one level due to publication bias: three out of ten studies reported analgesic duration. 6 Downgraded one level due to publication bias: four out of ten studies reported side effects. | ||||||
| Morphine compared with NSAIDs for pain control after knee arthroscopy | ||||||
| Patient or population: patients undergoing knee arthroscopy Comparison: NSAIDs administered via the knee joint | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| NSAIDs | Morphine | |||||
| Pain intensity VAS score | The mean pain score in the NSAIDs groups ranged from | The mean pain score in the morphine groups was | 80 | ⊕⊝⊝⊝ | ||
| Pain intensity VAS score | The mean pain score in the NSAIDs groups ranged from | The mean pain score in the morphine groups was | 80 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score | The mean pain score in the NSAIDs groups ranged from | The mean pain score in the morphine groups was | 80 | ⊕⊕⊝⊝ | ||
| Analgesia duration | See comment | See comment | Not estimable | 50 | ⊕⊕⊝⊝ | The data were not pooled. |
| Adverse events | Study population | RR 0.75 (0.19 to 3.04) | 120 | ⊕⊕⊕⊝ | ||
| 67 per 1000 | 49 per 1000 | |||||
| Moderate | ||||||
| 40 per 1000 | 29 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to risk of bias: one of the included studies (Guler 2002) was of low quality and has potential risk of bias. 2 Downgraded one level due to imprecision: the results showed wide confidence intervals. 3 Downgraded one level due to imprecision: wide confidence intervals. 4 Downgraded one level due to publication bias: three out of ten studies reported analgesic duration. 5 Downgraded one level due to publication bias: only one study reported analgesic duration. 6 Downgraded one level due to risk of bias: one study (Guler 2002) was of low quality. | ||||||
| 1 mg morphine compared with 2 mg/4 mg/5 mg morphine for pain control after knee arthroscopy | ||||||
| Patient or population: patients undergoing knee arthroscopy Comparison: 2 mg/5 mg morphine administered via the knee joint | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| 2 mg / 4 mg/5 mg morphine | 1 mg morphine | |||||
| Pain intensity VAS score 1 mg morphine vs 2 mg morphine | The mean pain score in the 2 mg morphine groups ranged from | The mean pain score in the 1 mg morphine groups was | 105 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score 0‐10 cm VAS score. Scale from: 0 to 10. | The mean pain score in the 2 mg morphine groups ranged from | The mean pain score in the 1 mg morphine groups was | 105 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score 0‐10 cm VAS score. Scale from: 0 to 10. | The mean pain score in the 2 mg morphine groups is 0.45 cm | The mean pain score in the 1 mg morphine groups was | 45 | ⊕⊕⊝⊝ | ||
| Analgesia duration 1 mg morphine vs 2 mg morphine | See comment | See comment | Not estimable | 60 | ⊕⊕⊕⊝ | The data were not pooled. |
| Adverse events 1 mg morphine vs 2 mg morphine | See comment | See comment | Not estimable | None | Not estimable | The were no data available. |
| Pain intensity VAS score 0‐10 cm VAS score. Scale from: 0 to 10. | The mean pain score in the 5 mg morphine groups ranged from | The mean pain score in the1 mg morphine groups was | 67 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score 0‐10 cm VAS score. Scale from: 0 to 10. | The mean pain score in the 5 mg morphine groups ranged from | The mean pain score in the 1 mg morphine groups was | 67 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score 0‐10 cm VAS score. Scale from: 0 to 10. | The mean pain score in the 5mg morphine groups ranged from | The mean pain score in the1mg morphine groups was | 67 | ⊕⊕⊝⊝ | ||
| Analgesia duration 1 mg morphine vs 4 mg/5 mg morphine | See comment | See comment | Not estimable | 24 | ⊕⊕⊕⊝ | The data were not pooled. |
| Adverse events 1 mg morphine vs 4 mg/5 mg morphine | See comment | See comment | Not estimable | None | Not estimable | The were no data available. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to publication bias: one out of three studies only presented data as figures and no usable data were available. 2 Downgraded one level due to imprecision: the results showed wide confidence intervals. 3 Downgraded one level due to publication bias: only one study reported analgesic duration. 4 Downgraded one level due to risk of bias: one of the included studies (Kanbak 1997) was of low quality. 5 Downgraded one level due to imprecision: imprecision arising from the small sample size. 6 Downgraded one level due to publication bias: only one study reported analgesic duration. | ||||||
| IA morphine compared with IM morphine for pain control after knee arthroscopy | ||||||
| Patient or population: patients undergoing knee arthroscopy Comparison: morphine administered intra‐muscularly | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| IM morphine | IA morphine | |||||
| Pain intensity VAS score | The mean pain score in the IM morphine groups ranged from | The mean pain score in the IA morphine groups was | 72 | ⊕⊝⊝⊝ | ||
| Pain intensity VAS score | The mean pain score in the IM morphine groups ranged from | The mean pain score in the IA morphine groups was | 72 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score | The mean pain score in the IM morphine groups is | The mean pain score in the IA morphine groups was | 39 | ⊕⊕⊝⊝ | ||
| Analgesia duration | See comment | See comment | Not estimable | None | Not estimable | The were no data available. |
| Adverse events | See comment | See comment | Not estimable | None | Not estimable | The were no data available. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to risk of bias: four out of five studies are of low quality. 2 Downgraded one level due to publication bias: only two out of five studies have usable data for meta‐analysis. 3 Downgraded one level due to imprecision: wide confidence intervals. 4 Downgraded one level due to publication bias: only one out of five studies have usable data for meta‐analysis. | ||||||
Background
Description of the condition
Knee arthroscopy is a very common procedure performed as day surgery and is associated with postoperative pain (Joshi 1992). The incidence of moderate or severe pain within an hour after knee arthroscopy is around 60%. Baseline scores are about 50 mm on the visual analogue scale (VAS) 10 minutes after test drug injection. However, pain scores quickly decreased to about 35 mm by 30 minutes and less than 5 mm by 12 hours (Solheim 2006). Women report more pain after knee arthroscopy than men (Rosseland 2004b). Adequate postoperative analgesia may accelerate the patient's return to normal activity.
Description of the intervention
Many trials have tried to find an ideal regimen which provides sufficient postoperative analgesia with fewer adverse events, including intra‐articular (IA) anaesthetics and analgesics for postoperative pain relief. The spinal or intravenous (IV) administration of morphine may cause side effects such as respiratory depression, sedation, dependence, pruritus and urinary retention. However, the adverse events of peripheral IA morphine administration were mild or absent. Morphine may therefore be a promising IA agent that is without obvious central side effects (Sawynok 2003). IA injection of morphine has been widely studied for its simplicity, safety and efficacy.
Opioid binding sites have been identified within synovial tissue, implying that the analgesic effect of morphine may be locally mediated (Khoury 1992). When given at the end of arthroscopic surgery, IA morphine could reduce postoperative pain through peripheral opioid receptors (Stein 1991). It has also been reported to reduce pain through other pathways (Kalso 1997) such as inflammatory reaction (Likar 1998; Stein 1995; Stein 1999). However, different opinions exist as to the postoperative effect of peripheral opioids. The reported dosages of IA morphine in studies vary from 0.5 mg to 5 mg (Joshi 1993). Stein 1991 reported that a dose of 1 mg morphine showed analgesic efficacy, whereas a dose of 0.5 mg did not. Allen 1993 reported that 2 mg morphine showed a better analgesic effect than 1 mg, but no dose response was detected in two other studies (Heine 1994; Laurent 1994). Other controlled trials, however, have failed to show any analgesic effect of morphine compared with placebo (Aasbø 1996; Drosos 2002; Gupta 1999; Ruwe 1995; Soderlund 1997).
In addition to opiates, many other interventions have been widely studied for the reduction of postoperative pain following knee arthroscopy. Local anaesthetics (such as bupivacaine, ropivacaine, carbocaine, lidocaine and prilocaine), non‐steroidal anti‐inflammatory drugs ((NSAIDs) such as ketorolac and tenoxicam) and other interventions (such as magnesium, clonidine, neostigmine and ketamine) have been intensely studied.
How the intervention might work
Opioid receptors exist on peripheral terminals of primary afferent neurons, demonstrated functionally and morphologically in Bartho 1990 and Stein 1990. As a μ‐opioid receptor agonist, morphine is effective in producing peripheral analgesia. Morphine activates peripheral opioid receptors, resulting in their interactions with G‐proteins and a decrease in cyclic adenosine monophosphate (cAMP) in sensory nerve terminals, an increase in K+ efflux and a decrease of Ca2+ entry. Thus, the excitability of the peripheral nerve terminal, the propagation of action potentials and release of neuropeptides are attenuated (Sawynok 2003).
Why it is important to do this review
Several systematic reviews have investigated IA morphine for the control of pain after knee surgery, however, consensus on the analgesic effect is still lacking. A previously published qualitative systematic review (Kalso 1997) showed that IA morphine was effective in reducing postoperative pain intensity and the consumption of rescue analgesics. All knee surgeries were included in the review, however, and it failed to focus on the effect of IA morphine on pain relief after knee arthroscopy. Also, no quantitative analysis of pooled data was performed here, nor in the authors' second systematic review on this topic (Kalso 2002). In another systematic review, variability was found not only between studies but also within one study (patient variability) (Gupta 2001). By calculating the weighted mean difference (WMD) of pain scores between treatment groups, Moiniche 1999 found that there was weak evidence for a reduction of postoperative pain after IA instillation of local anaesthetics. More trials comparing morphine and other interventions for knee arthroscopy were available recently and they added new knowledge to inform clinical practice (Rosseland 2003; Rosseland 2004a; Rosseland 2004b). Evidence is still lacking as to whether IA opioids offer clinically relevant pain relief. In light of the existing controversy, this systematic review aimed to investigate the analgesic effect of single dose IA morphine compared with other interventions in the management of pain control after knee arthroscopy.
Objectives
To evaluate the relative effects on pain relief and adverse events of IA morphine given for pain control after knee arthroscopy compared with placebo, other analgesics (local anaesthetics, non‐steroidal anti‐inflammatory drugs (NSAIDs), other opioids) and other routes of morphine administration.
Methods
Criteria for considering studies for this review
Types of studies
We included studies fulfilling the following selection criteria in this systematic review:
-
randomised, double‐blind controlled trials;
-
studies comparing single dose IA morphine with other interventions for the treatment of postoperative pain after knee arthroscopy; and
-
studies with more than 10 participants in each group.
We excluded the following studies:
-
studies in which spinal or epidural anaesthesia was used; and
-
studies whose primary aim was to assess the analgesic effect of IA morphine on chronic pain.
Types of participants
We included participants of either gender, aged 15 years or older, and undergoing knee arthroscopy.
Types of interventions
IA morphine versus any other interventions or administration methods:
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IA morphine versus placebo;
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IA morphine versus local anaesthetic agents (such as bupivacaine, ropivacaine, carbocaine, lidocaine and prilocaine);
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IA morphine versus NSAIDs (such as ketorolac and tenoxicam);
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different doses of IA morphine;
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IA morphine versus intravenous (IV) or intra‐muscular (IM) morphine;
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IA morphine versus other opioids.
Types of outcome measures
We included the following outcomes.
Primary outcomes
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Patient‐reported postoperative pain intensity (a 0 ‐ 10 cm VAS score).
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Use of supplementary analgesic (number of participants using rescue analgesics, time to first rescue analgesics, analgesic drug counts, patient‐controlled analgesia opioid consumption, etc.).
Secondary outcomes
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Adverse events.
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Withdrawals.
Search methods for identification of studies
Electronic searches
We searched CENTRAL (The Cochrane Library, Issue 4, 2015), MEDLINE via Ovid (January 1966 to May 2015), EMBASE via Ovid (January 1988 to May 2015). Please see Appendix 1; Appendix 2; Appendix 3 for the database search strategies. Filters designed to limit the searches to RCTs were added to the MEDLINE and EMBASE strategies.
Searching other resources
Reference lists
We sought additional studies from the references of retrieved randomised trials, meta‐analyses and systematic reviews.
Unpublished studies
We searched trials registries for ongoing trials. We searched three web sites: the metaRegister of controlled trials (www.controlled-trials.com/mrct), clinicaltrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/) up to May 2015.
Language
The search identified all relevant studies irrespective of language. We assessed non‐English language papers and translated as necessary.
Data collection and analysis
Selection of studies
Two authors independently assessed the eligibility of studies included in the review, and another author checked these results. For the studies that were reported several times, we used the first edition and added data from the secondary references to the first study to extract full data. We resolved any disagreement by discussion.
Data extraction and management
Two authors independently extracted data from each identified study and recorded data on a standardised data extraction form. We resolved any disagreement by discussion with a third author when necessary.
Assessment of risk of bias in included studies
Two authors assessed risk of bias for each study independently, based on the methods used to generate allocation sequence, allocation concealment, blinding, follow‐up, selective reporting and group size according to the 'Risk of bias' tool (Kjaergard 2001; Moher 1998; Schulz 1995; Higgins 2011a).
We assessed the methods used to deal with incomplete data as: low risk of bias (< 10% of participants did not complete the study or used 'baseline observation carried forward' analysis, or both); unclear risk of bias (used 'last observation carried forward' analysis); and high risk of bias (used 'completer' analysis).
"Size" was added to the 'Risk of bias' table. We assessed studies as low risk of bias (≧ 200 participants per treatment arm); unclear risk of bias (50 to 199 participants per treatment arm); and high risk of bias (< 50 participants per treatment arm).
We resolved any disagreement by discussion.
Dealing with missing data
We did not contact authors for missing data. We followed intention‐to‐treat principles. In some studies, the exact mean, standard deviation (SD) and standard error (SE) of pain scores were not reported or were difficult to decipher when results were presented in figures. In this situation, two review authors independently estimated the visual analogue scale (VAS) score presented in the figures in each study using Engauge Digitizer 4.1 (Lan 2010; Ma 2012) and achieved an agreement on the mean ± SE or SD (Gupta 2001). When the number of participants enrolled and the number of participants who reported outcomes were different, we noted this in the 'Characteristics of included studies' table. If the exclusions of participants was justifiable, we would use available data from the studies; if withdrawal of participants were not justifiable, we would carry out intention to treat (ITT) analysis.
Assessment of heterogeneity
We tested the heterogeneity between studies using the Chi2 test (with P < 0.1 indicating significant heterogeneity) and the I2 statistic, which described the proportion of variability due to heterogeneity (Higgins 2003). When P > 0.1, we carried out the meta‐analysis using a fixed‐effect model; otherwise we used a random‐effects model.
Data synthesis
Quantitative analysis
We performed a statistical analysis of outcomes. We merged both dichotomous and continuous data quantitatively in meta‐analysis.
Dichotomous data
For dichotomous data, such as the number of participants who suffered from adverse events, we calculated the risk ratio (RR) using Review Manager software (RevMan) 5.3 (RevMan 2014).
Continuous data
For continuous data, such as postoperative VAS score, analgesic duration of intervention drugs, we calculated mean differences (MDs). We applied a random‐effects or fixed‐effect model to assess outcomes, depending on the statistical heterogeneity among studies.
Qualitative analysis
Different analgesics were used to relieve postoperative pain and many studies did not report the exact doses consumed. Consequently, statistical analyses were not always possible. In situations where the data extracted from the original studies were insufficiently similar, we did not conduct a meta‐analysis but produced a qualitative description of the outcome study by study.
Quality of the evidence
Two review authors independently rated the quality of the outcomes pain intensity, analgesia duration and adverse events. We used the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) system to rank the quality of the evidence using the GRADEprofiler Guideline Development Tool software (GRADEPro GDT 2015), and the guidelines provided in Chapter 12.2 of the CochraneHandbook for Systematic Reviews of Interventions (Higgins 2011b).
The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The GRADE system uses the following criteria for assigning grade of evidence:
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High = further research is very unlikely to change our confidence in the estimate of effect;
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Moderate = further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate;
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Low = further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate;
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Very low = any estimate of effect is very uncertain.
We decreased grade if:
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Serious (‐1) or very serious (‐2) limitation to study quality;
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Important inconsistency (‐1);
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Some (‐1) or major (‐2) uncertainty about directness;
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Imprecise or sparse data (‐1);
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High probability of reporting bias (‐1).
'Summary of findings' table
We included 'Summary of findings' tables to present the main findings in a transparent and simple tabular format. In particular, we included key information concerning the quality of evidence, the magnitude of effect of the interventions examined, and the sum of available data on the outcomes listed above.
Subgroup analysis and investigation of heterogeneity
We carried out subgroup analysis to assess clinical heterogeneity rather than statistical heterogeneity. We carried out separate analyses for the most important clinical parameters as follows.
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We identified three phases to assess postoperative pain: early phase (zero to two hours), medium phase (two to six hours) and late phase (six to 30 hours). We analysed the data from these different phases separately. Data of two hours and six hours were allocated to early phase and medium phase, respectively.
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Comparisons: different agents were used as the comparator regimens in various studies. We only quantitatively merged the studies with the same drug categories in meta‐analysis.
Sensitivity analysis
We performed sensitivity analysis to evaluate the effect of methodological characteristics (quality assessment) of studies on the results of the meta‐analysis.
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies.
Results of the search
We identified 724 studies through the initial electronic search. We scanned these studies and found 35 studies which could not be excluded by scrutiny of the title and abstract only. Of these, seven were further excluded for reasons cited in the Characteristics of excluded studies table. Twenty eight studies (29 reports) satisfied the inclusion criteria comparing morphine with placebo or other analgesics (Figure 1). Studies that met the inclusion criteria contained 2482 enrolled participants, with trial size varying from 33 to 320 participants.
Flowchart showing the stepwise screening of search results
Included studies
Twenty studies (21 reports) enrolled participants undergoing elective arthroscopic knee surgery of multiple procedures such as diagnostic arthroscopy, meniscectomy, excision of plicae, full arthroscopic lateral retinacular release, synovectomy and chondral debridement (Aasbø 1996; Akinci 2003; Alagol 2005; Allen 1993; Bjornsson 1994; Christensen 1996; Follak 2001; Franceschi 2001; Kazemi 2004; Khoury 1992; Kizilkaya 2005; Likar 1995; Likar 1999; Muller 2001; Raj 2004; Richardson 1997; Rosseland 2003a; Ruwe 1995; Solheim 2006; Varkel 1999; Wrench 1996). Six studies (Calmet 2004; De Andres 1998; Dierking 1994; Elkousy 2013; Kanbak 1997; Lyons 1995) only enrolled participants undergoing arthroscopic meniscectomy and one study (Guler 2002) only enrolled participants undergoing arthroscopic anterior cruciate ligament (ACL) reconstruction with hamstring tendons.
Some studies had both placebo and active drug as control, and some had more than one active comparator. Twenty studies included a placebo control, whereas 23 used an active drug in the control group. The active drugs relevant to our studies included bupivacaine (Aasbø 1996; Alagol 2005; Allen 1993; Bjornsson 1994; Calmet 2004; De Andres 1998; Follak 2001; Khoury 1992; Richardson 1997; Ruwe 1995), ropivacaine (Franceschi 2001; Muller 2001), tenoxicam (Alagol 2005; Guler 2002), tramadol (Akinci 2003; Likar 1995), sufentanil (Kazemi 2004), fentanyl (Varkel 1999), pethidine (Lyons 1995), morphine injected IV/IM (Christensen 1996; Dierking 1994; Raj 2004; Richardson 1997; Rosseland 2003a) and different doses of morphine (Allen 1993; Kanbak 1997; Kizilkaya 2005; Likar 1999). Morphine was used from 1 mg to 10 mg. Two hundred and seventy three participants took a 1 mg dose (Allen 1993; Bjornsson 1994; Calmet 2004; De Andres 1998; Kanbak 1997; Khoury 1992; Kizilkaya 2005; Likar 1995; Likar 1999; Muller 2001; Richardson 1997; Wrench 1996), 178 took 2 mg (Alagol 2005; Allen 1993; Dierking 1994; Franceschi 2001; Guler 2002; Likar 1999; Rosseland 2003a; Ruwe 1995), 65 took 3 mg (Aasbø 1996; Kazemi 2004; Varkel 1999), 19 took 4 mg (Likar 1999), 325 took 5 mg (Akinci 2003; Bjornsson 1994; Christensen 1996; Follak 2001; Kanbak 1997; Kizilkaya 2005; Lyons 1995; Muller 2001; Richardson 1997; Solheim 2006), and 39 took 10 mg (Raj 2004).
Pain was rated using VAS in 26 trials, and a verbal rating scale (VRS) was used in six ( Akinci 2003; Christensen 1996; De Andres 1998; Rosseland 2003a; Solheim 2006; Wrench 1996). One study (Bjornsson 1994) assessed pain intensity using a modified VAS score, which was different from the conventional VAS score. In the modified score, "10" corresponded to "severe pain" instead of the conventional ''worst imaginable'' to increase the sensitivity of the scale. We excluded its results of VAS score from meta‐analysis. For those presenting both VAS at rest and VAS with movement, we only abstracted VAS at rest for meta‐analysis. However, the studies did not provide all the outcomes of interest. Some studies gave the central tendency of VAS as median, some presented mean values without SD, and some showed results in figures. We abstracted the data from figures using Engauge Digitizer 4.1. We did not include data presented as median and interquartile range in the meta‐analysis. Different analgesics and treatment regimens were employed for rescue medication, such as tylenol, paracetamol, tramadol, ketorolac, and metamizol, so a meta‐analysis of the rescue medication was not considered feasible.
Excluded studies
We excluded four studies (see Characteristics of excluded studies). One trial used spinal anaesthesia rather than general anaesthesia (Alvarez‐Cabo 1998). Two trials included fewer than 10 participants in the intervention group (Lehrberger 1994; Stein 1991). One trial included participants under 15 years old (De Andres 1993). Three studies were classified in Characteristics of studies awaiting classification because full texts were unavailable through database searching, handsearching or inter‐library loan (Altan 1994; Uzma 1997; VanNess 1994).
Risk of bias in included studies
All the included studies were prospective randomised double‐blind controlled trials (see Characteristics of included studies). We completed a 'Risk of bias' table and results were presented graphically in Figure 2 and summarised in Figure 3.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
All of the studies were described as 'randomised', and nine studies were of low risk (seven were randomised using a random table or a list of random numbers, two had randomisation stratified by a computerised allocation schedule). One study was assessed as high risk for its randomisation methods, which allocated patients according to the odd or even account number given on the day of surgery. Randomisation technique was not described in 18 studies, which were assessed as unclear risk. Allocation concealment was of low risk in 10 studies and of unclear risk in 18 studies. Although some studies failed to report the methods used to ensure randomisation and allocation concealment adequately, we included all of the studies in the analysis. We did sensitivity analysis to measure the effects of methodological quality.
Blinding
Twenty‐seven included trials were double‐blind and one was single‐blind. Thirteen trials stated the methods to maintain blindness of participants and personnel and were of low risk. Four studies stated the blinding of outcome assessment and were assessed as unclear risk.
Incomplete outcome data
Twenty‐six of the included studies were assessed as low risk and two studies as high risk. Seven studies (Aasbø 1996; Christensen 1996; Dierking 1994; Likar 1999; Lyons 1995; Raj 2004; Solheim 2006) reported the exact number of participants lost to follow‐up. Five studies (Aasbø 1996; Christensen 1996; Likar 1995; Lyons 1995; Raj 2004) had less than 10% of participants who did not complete the study and two studies (Dierking 1994; Likar 1999) had more than 10% withdrawals. Other studies did not mention dropouts. They included all the participants in the analysis as seen from the results section.
Selective reporting
Five studies (Akinci 2003; Alagol 2005; Calmet 2004; De Andres 1998; Raj 2004) were assessed as low risk and four studies (Guler 2002; Lyons 1995; Ruwe 1995; Wrench 1996) were assessed as high risk, while the other nineteen studies were assessed as unclear risk of selective reporting bias.
Other potential sources of bias
We considered study size as a potential source of bias because most of the included studies were small‐sized. Studies with fewer than 10 participants in each group were excluded. Twenty seven in 28 studies had fewer than 50 participants in each group, which were rated as high risk. These studies were all of small size and thus made the conclusions less robust. Only one study had a group size larger than 50 participants.
Effects of interventions
See: Summary of findings 1 Morphine compared with placebo for pain control after knee arthroscopy; Summary of findings 2 Morphine compared with bupivacaine for pain control after knee arthroscopy; Summary of findings 3 Morphine compared with NSAIDs for pain control after knee arthroscopy; Summary of findings 4 Different doses of morphine for pain control after knee arthroscopy; Summary of findings 5 IA morphine compared with IM morphine for pain control after knee arthroscopy
We used pain intensity VAS score and use of supplementary analgesia (analgesia duration) as primary outcomes to assess analgesic effects of IA morphine, and adverse events and withdrawals as secondary outcomes to assess the safety of IA morphine.
Primary outcomes: patient‐reported postoperative pain intensity and use of supplementary analgesic
1. Morphine versus placebo
Twenty studies (20 reports) with 2066 participants compared morphine directly with placebo (Aasbø 1996; Akinci 2003; Alagol 2005; Bjornsson 1994; Calmet 2004; De Andres 1998; Follak 2001; Franceschi 2001; Guler 2002; Kanbak 1997; Kazemi 2004; Likar 1999; Lyons 1995; Muller 2001; Richardson 1997; Rosseland 2003a; Ruwe 1995; Solheim 2006; Varkel 1999; Wrench 1996). Thirteen of these studies found a beneficial effect of morphine (Akinci 2003; Alagol 2005; De Andres 1998; Follak 2001; Franceschi 2001; Guler 2002; Kanbak 1997; Kazemi 2004; Likar 1999; Lyons 1995; Muller 2001; Richardson 1997; Varkel 1999) whereas seven others did not find any beneficial effect (Aasbø 1996; Bjornsson 1994; Calmet 2004; Rosseland 2003a; Ruwe 1995; Solheim 2006; Wrench 1996). Among eight studies that compared 1 mg morphine with placebo (Bjornsson 1994; Calmet 2004; De Andres 1998; Kanbak 1997; Likar 1999; Muller 2001; Richardson 1997; Wrench 1996), four studies found a better analgesia effect of 1 mg morphine (De Andres 1998; Likar 1999; Muller 2001; Richardson 1997). Of the six studies that compared 2 mg morphine with placebo (Alagol 2005; Franceschi 2001; Guler 2002; Likar 1999; Rosseland 2003a; Ruwe 1995), four studies showed better analgesia of 2 mg morphine (Alagol 2005; Franceschi 2001; Guler 2002; Likar 1999).
Of studies comparing morphine with placebo, nine in 20 studies had suitable data for meta‐analysis (Calmet 2004; De Andres 1998; Kanbak 1997; Kazemi 2004; Likar 1999; Muller 2001; Richardson 1997; Varkel 1999; Wrench 1996), including seven studies comparing 1 mg morphine with placebo and two studies comparing 2 mg morphine with placebo. We included seven studies (297 participants) comparing 1 mg morphine with placebo in meta‐analysis. There was no difference between 1 mg IA morphine and placebo in pain intensity (VAS score) at early, medium or late phases (Figure 4). The MD and 95% confidence interval (CI) of resting pain was MD ‐0.50 (95% CI, ‐1.15 to 0.14), MD ‐0.47 (95% CI, ‐1.09 to 0.14), and MD ‐0.88 (95% CI, ‐1.81 to 0.04), respectively.
Forest plot of comparison: 1 pain intensity VAS score, outcome: 1.1 1mg morphine vs placebo.
Eleven out of 20 studies reported time to first request of supplementary analgesics (Aasbø 1996; Akinci 2003; Alagol 2005; Calmet 2004; De Andres 1998; Follak 2001; Franceschi 2001; Kanbak 1997; Likar 1999; Kizilkaya 2005; Lyons 1995) and 17 out of 20 studies reported consumption of rescue medication (Aasbø 1996; Akinci 2003; Alagol 2005; Calmet 2004; Follak 2001; Guler 2002; Kanbak 1997; Kazemi 2004; Likar 1999; Lyons 1995; Muller 2001; Richardson 1997; Rosseland 2003a; Ruwe 1995; Solheim 2006; Varkel 1999; Wrench 1996). However, most studies did not present the exact dosages consumed and the number of different analgesic regimens was large. The data could not be subjected to any statistical analysis, so we summarised the results of each study. Three of 10 studies showed a significantly longer time to first analgesic request in the IA morphine group than the placebo group (Alagol 2005; Franceschi 2001; Kanbak 1997) while the remaining seven studies did not find a significant difference. Meta‐analysis of three studies (Alagol 2005; De Andres 1998; Kanbak 1997) indicated no difference between the IA morphine and placebo groups of time to first analgesic request. An I² statistic of 100% represented highly inconsistent findings across studies, and might indicate an error in the data. Seven studies showed a decrease in the postoperative consumption of analgesics in the IA morphine group (Alagol 2005; Kanbak 1997; Kazemi 2004; Likar 1999; Muller 2001; Richardson 1997; Varkel 1999), and four studies found that the number of participants who consumed supplementary analgesics in the IA morphine group was lower than the control group (Aasbø 1996; Calmet 2004; Follak 2001; Lyons 1995). Seven of 13 studies with significant differences favouring morphine also showed a decreased consumption of analgesics in the IA morphine group (Alagol 2005; Follak 2001; Kanbak 1997; Kazemi 2004; Likar 1999; Muller 2001; Varkel 1999), while in three studies analgesic consumption was equivalent between the IA morphine group and the placebo group (Akinci 2003; Lyons 1995; Richardson 1997).
We judged the quality of evidence for pain intensity VAS score, for morphine versus placebo, to be low. We downgraded the quality of evidence by two levels due to risk of bias and publication bias.
We judged the quality of evidence for analgesia duration, for morphine versus placebo, to be low. We downgraded the quality of evidence by two levels due to risk of bias and publication bias.
2. Morphine versus local anaesthetics
Twelve studies (12 reports) compared IA morphine with IA local anaesthetics (Aasbø 1996; Alagol 2005; Allen 1993; Bjornsson 1994; Calmet 2004; De Andres 1998; Follak 2001; Franceschi 2001; Khoury 1992; Muller 2001; Richardson 1997; Ruwe 1995). Among the 10 studies that compared IA morphine with IA bupivacaine, five studies found a better analgesia effect of bupivacaine (Allen 1993; De Andres 1998; Follak 2001; Khoury 1992; Ruwe 1995) and the other five studies did not find significant differences. Of the six studies comparing 1 mg morphine with bupivacaine, three studies found IA bupivacaine provided better analgesia than IA morphine (Allen 1993; De Andres 1998; Khoury 1992), and the other three studies did not find a difference (Bjornsson 1994; Calmet 2004; Richardson 1997). Allen 1993 indicated that participants who received 1 mg IA morphine in combination with 0.25% bupivacaine provided superior postoperative analgesia for up to 24 hours after knee arthroscopy versus morphine or bupivacaine alone. Meta‐analysis of six studies comparing IA morphine with IA bupivacaine found no better analgesic effects of morphine (Figure 5). The MD and 95% CI of pain at rest was MD 1.43 (95% CI 0.49 to 2.37; participants = 248; studies = 5); at early phase, MD 0.45 (95% CI ‐0.47 to 1.36; participants = 330; studies = 6), and MD ‐0.71 (95% CI ‐1.23 to ‐0.19; participants = 270; studies = 5), respectively (summary of findings Table 2). The results were highly heterogeneous because of the small size of the included studies. Three studies (Alagol 2005; Allen 1993; De Andres 1998) reported time to first analgesic request, and two studies (Allen 1993; De Andres 1998) found morphine had long analgesic duration. Two studies compared ropivacaine with morphine (Franceschi 2001; Muller 2001), where no significant difference of analgesic effect was found in one study (Franceschi 2001), and the other study (Muller 2001) favoured ropivacaine.
Forest plot of comparison: 1 pain intensity VAS score, outcome: 1.2 1mg morphine vs bupivacaine.
We judged the quality of evidence for pain intensity VAS score, for morphine versus bupivacaine, to be low. We downgraded the quality of evidence by two levels due to risk of bias and publication bias.
We judged the quality of evidence for analgesia duration, for morphine versus bupivacaine, to be moderate. We downgraded the quality of evidence by one level due to publication bias.
3. Morphine versus NSAIDs
Three studies (Alagol 2005; Calmet 2004; Guler 2002) compared morphine with NSAIDs. Two studies (Alagol 2005; Guler 2002) compared 20 mg tenoxicam with 2 mg morphine and no difference was found in VAS score in meta‐analysis. One study (Alagol 2005) suggested tenoxicam had better analgesic effects and a lower analgesic consumption compared with morphine. The other study (Alagol 2005) did not find a difference on VAS score between tenoxicam and morphine, while the tenoxicam group consumed fewer analgesics than the morphine group. The available data were few, and did not provide robust evidence. Another study (Calmet 2004) compared morphine with ketorolac and concluded that ketorolac was more effective than morphine in pain relief.
We judged the quality of evidence for pain intensity VAS score, for morphine versus NSAIDs, to be very low. We downgraded the quality of evidence by three levels due to risk of bias and imprecision.
We judged the quality of evidence for analgesia duration, for morphine versus NSAIDs, to be low. We downgraded the quality of evidence by two levels due to risk of bias and publication bias.
4. Different doses of morphine
Four studies (four reports) compared different doses of IA morphine (Allen 1993; Kanbak 1997; Kizilkaya 2005; Likar 1999), of which three studies (Allen 1993; Kanbak 1997; Likar 1999) had usable data for meta‐analysis. Results of one study (Kizilkaya 2005) were presented as figures, which could not be used in meta‐analysis. No difference was found between 1 mg morphine and 2 mg morphine in meta‐analysis of two studies (Allen 1993; Likar 1999). Two studies (Kanbak 1997; Likar 1999) compared 1 mg morphine with 4 mg/5 mg morphine and meta‐analysis showed intensity of pain was lower in the 4 mg/5 mg morphine group than in the 1 mg morphine group at early, medium and late phases (Figure 6). Two studies (Kanbak 1997; Kizilkaya 2005) concluded that the analgesic effects of morphine were dose‐dependent and that 5 mg morphine might have systemic effects on pain relief in participants. Two studies reported analgesic duration, and no difference was found among different doses of morphine. The limited number of studies might bias the conclusion. The number of participants included was small and the differences between groups were not clinically significant. The limited number of studies on dose effects suggests there is a need for more clinical trials.
Forest plot of comparison: 1 pain intensity VAS score, outcome: 1.6 1mg morphine vs 5mg morphine.
We judged the quality of evidence for pain intensity VAS score, for 1 mg morphine vs 2 mg morphine, to be low. We downgraded the quality of evidence by two levels due to publication bias and imprecision.
We judged the quality of evidence for analgesia duration, for 1 mg morphine vs 2 mg morphine, to be moderate. We downgraded the quality of evidence by one level due to publication bias.
5. Different routes of administration
Five studies (five reports) compared different administration routes of morphine, including IA injection, IV injection and IM injection (Bjornsson 1994; Christensen 1996; Dierking 1994; Raj 2004; Richardson 1997). Of the four studies that compared IA morphine with IM morphine, three studies concluded that no significant difference in pain scores or in requirements for supplemental morphine was observed between participants receiving IA versus IM morphine (Bjornsson 1994; Christensen 1996; Dierking 1994). Only one study concluded that IA morphine provided better analgesia than the same dose of IM morphine and indicated a peripheral mechanism of IA morphine (Raj 2004). Two studies (72 participants) were included in meta‐analysis and no difference was found in pain intensity between IA and IM morphine (Analysis 1.4). The study comparing IA morphine with IV morphine indicated that IA morphine group had a lower VAS score and fewer additional analgesics (Richardson 1997).
We judged the quality of evidence for pain intensity VAS score at early phase (0 ‐ 2 hours), for IM morphine versus IA morphine, to be very low. We downgraded the quality of evidence by three levels due to risk of bias, publication bias and imprecision.
No data were available for analgesia duration.
6. Morphine versus other opioids
IA morphine was compared with tramadol, sufentanil, fentanyl and pethidine (Akinci 2003; Kazemi 2004; Likar 1995; Lyons 1995; Varkel 1999). Sufentanil, fentanyl and pethidine showed improved analgesia compared to morphine (Kazemi 2004; Lyons 1995; Varkel 1999). IA injection of morphine and sufentanil both reduced the post‐arthroscopic‐knee procedural pain and the need for supplementary analgesics, but sufentanil 5 µg was more effective than morphine 3 mg (Kazemi 2004). Better postoperative analgesia was achieved with 50 µg IA fentanyl than with 3 mg IA morphine (Varkel 1999). The local anaesthetic effect of pethidine may have been responsible for the improved early analgesia, but its duration of action appeared to be less than that of morphine (Lyons 1995). Of the two studies that compared morphine with tramadol, one study found no difference between 5 mg morphine and 50 mg tramadol (Akinci 2003); while the other showed better analgesia of 1 mg morphine compared with 10 mg tramadol (Likar 1995). Because of the limited number of studies, no meta‐analysis was carried out.
Secondary outcomes: adverse events and withdrawals
In this review, twelve studies (13 reports) reported incidence of adverse events, and no difference was reported between groups. Eleven out of 20 studies comparing morphine with placebo reported side effects and nine studies (364 participants) were included in the meta‐analysis. No statistical difference was obtained regarding the incidence of side effects between IA morphine and placebo in meta‐analysis (Analysis 3.1). Two studies showed significant differences between IA morphine and IV morphine/ropivacaine. One study (Franceschi 2001) reported that three participants (10%) of the IA morphine group complained of nausea while no side effects were noted in ropivacaine group. One study (Richardson 1997) reported that the incidence of nausea was larger in the IV morphine group than in the IA morphine group.
We judged the quality of evidence for adverse events, for morphine versus placebo, to be low. We downgraded the quality of evidence by two levels due to risk of bias and publication bias.
We judged the quality of evidence for adverse events, for morphine versus bupivacaine, to be moderate. We downgraded the quality of evidence by one level due to publication bias.
We judged the quality of evidence for adverse events, for morphine versus NSAIDs, to be moderate. We downgraded the quality of evidence by one level due to risk of bias.
Seven of 28 studies reported participants' withdrawal. Five studies (Aasbø 1996; Christensen 1996; Likar 1995; Lyons 1995; Raj 2004) had less than 10% of participants who did not complete the study and two studies (Dierking 1994; Likar 1999) had more than 10% withdrawals. Only one study (Raj 2004) reported the allocated group of the participants lost to follow‐up. One participant withdrew from the IM morphine group while no participants withdrew from the IA morphine group. There were not enough data for meta‐analysis.
Sensitivity analysis
We excluded nine low‐quality studies (743 participants) from meta‐analysis (Aasbø 1996; Christensen 1996; Dierking 1994; Elkousy 2013; Follak 2001; Guler 2002; Kanbak 1997; Khoury 1992; Likar 1995) to measure the effects of methodological quality. The pain intensity VAS score comparisons of 1 mg IA morphine with placebo and 1 mg morphine with bupivacaine did not change.
Discussion
Summary of main results
This review evaluated the relative effects on pain intensity and adverse events of IA morphine after knee arthroscopy. We compared IA morphine with placebo, active analgesics (local anaesthetics, NSAIDs, other opioids) and other routes of morphine administration. We found that IA morphine did not show beneficial effects in pain intensity compared with placebo. IA morphine was not better than IA bupivacaine, NSAIDs, sufentanil, fentanyl and pethidine in pain control. The comparison of effects between morphine and bupivacaine at different time points presented for the comparison of morphine and bupivacaine varied (zero to two hours favoured bupivacaine but this effect had reversed at 24 to 30 hours). The evidence was low quality and the relative effects of the interventions listed were uncertain. The conclusion is not robust because some of the included studies were of low quality and were poorly reported.
Of the 20 studies that compared IA morphine with placebo, we included nine studies with suitable data in the meta‐analysis, which did not show a difference between 1 mg IA morphine and placebo in pain intensity at early, medium or late phases. There was low quality evidence for IA morphine compared with IA bupivacaine, NSAIDs, sufentanil, fentanyl and pethidine, and the relative effects are uncertain. Meta‐analysis indicated no difference between IA morphine and placebo/bupivacaine in time to first analgesic request. None of the included studies showed any statistical difference regarding the incidence of adverse events between IA morphine and placebo.
Overall completeness and applicability of evidence
We searched for published and ongoing trials on IA morphine to identify all the relevant studies. We could only extract useful data from 17 of the 28 included studies. Our evidence showed that IA morphine given after knee arthroscopy did not have beneficial effects in pain relief compared with placebo, and IA morphine was not better than IA bupivacaine, NSAIDs, sufentanil, fentanyl or pethidine. We could not find any robust evidence to support the analgesic effects of IA morphine.
Included studies enrolled participants undergoing elective arthroscopic knee surgery of multiple procedures, such as diagnostic arthroscopy, meniscectomy, excision of plicae, full arthroscopic lateral retinacular release, synovectomy, and chondral debridement, covering most of the knee arthroscopic surgeries. The number of studies favouring morphine exceeded the number of studies without significant difference.
More than half of the included studies did not report adverse events. Of the studies reporting adverse events, we found no statistical difference regarding the incidence of side effects between IA morphine and placebo. No severe side effects of IA morphine were reported.
Quality of the evidence
This systematic review was limited by the quality of existing data. All the included studies were described as randomised and double‐blind, however, some studies failed to report the methods used to ensure randomisation and blinding adequately. In addition, we could not pool some data due to divergent outcome measurements and different types of rescue agents used in the studies. The group sizes of the included studies were small, which indicated low quality of the included studies. Some of the included RCTs with usable information were of low methodological quality. Lack of allocation concealment and blinding might be a source of bias which threatened the validity of the reported results. There was clinical heterogeneity among some trials, which resulted in high levels of statistical heterogeneity in some analyses. Most outcomes were assessed as low quality according to GRADE. Three full texts were unavailable and some outcomes were not fully reported, which might have had an impact on the quality of this review.
Potential biases in the review process
Thirty five studies appeared to satisfy the inclusion criteria through searching, but seven studies were not included in this review (see Figure 1). For example, despite our great efforts, three full texts were unavailable through database searching, handsearching or inter‐library loan (Altan 1994; Uzma 1997; VanNess 1994) (Characteristics of studies awaiting classification). The previously related published systematic reviews also did not include these three studies. Several studies were excluded from meta‐analysis because not enough data were presented in the text. Moreover, not all the included studies reported all the outcomes of interest. Two high‐quality studies only presented results as median and interquartile. The retrieved studies were heterogenous in data and the results of the meta‐analyses might then be less robust.
Agreements and disagreements with other studies or reviews
Four systematic reviews focusing on the same topic have been published previously. Three of them (Gupta 2001; Kalso 1997; Kalso 2002) came up with a positive conclusion that IA morphine might alleviate postoperative pain after knee arthroscopy, while one study found no analgesic effects of morphine compared with placebo (Rosseland 2004b). In the first review by Kalso in 1997, 33 RCTs published before 1996 were included, with no quantitative analysis of pooled data made. Seven RCTs from the included articles showed a significant analgesic effect of IA morphine compared with placebo. The study authors felt that sensitivity of analgesic measurement was important, based on the judgment that low pain intensity in the immediate postoperative period could render the studies insensitive (i.e. no significant difference). In the review, the effectiveness of internal sensitivity was defined as a significant difference between the active and placebo in pain intensity or total consumption of rescue analgesics, as reported by original studies. For example, bupivacaine as an active control in four studies showed a significantly lower VAS compared with placebo, and these four studies were considered sensitive (i.e. significant differences between groups), and the comparison between IA morphine and placebo can be made.
Later, bupivacaine was found to have no better analgesic effect than placebo, thus it was not suitable for testing study sensitivity. Therefore, in 2002, Kalso et al suggested a study was sensitive if VAS was above 3/10 in the control group. Fifteen of 25 trials were considered sensitive. The article concluded that IA morphine was superior to placebo, especially when a dose of 5 mg was used. However, the author also thought that a systemic effect still had to be considered with 5 mg of IA morphine.
In another systematic review (Gupta 2001), the authors did a quantitative analysis of data from 19 (of 45) studies and found an improvement in analgesia in the morphine group compared with placebo. However, in this review, the original articles included participants who underwent arthroscopic knee procedures under local, regional or general anaesthesia. Minor surgeries often cause less tissue damage and less postoperative pain, and spinal anaesthesia can provide longer lasting analgesia compared with general anaesthesia. Therefore, in our present systematic review, only patients under general anaesthesia were included.
Different from the above three reviews, the negative result from Rosseland 2004b suggested that, in properly controlled trials, there was no added analgesic effect of IA morphine compared with placebo alone. The authors thought that most trials with positive results were of low quality or had a small sample size, which must be interpreted cautiously because of the high likelihood of having a randomisation failure. The authors also considered that the definition of sensitive studies in previous systematic reviews (Kalso 1997; Kalso 2002) possibly introduced a bias, because it was difficult to document a baseline pain, making high pain intensity in the placebo group and the positive results simply an outcome of imbalanced allocation of participants.
Two studies compared IA morphine with placebo given to participants who experienced baseline pain of moderate to severe intensity after knee arthroscopy (Rosseland 2003a; Solheim 2006). They found no difference between groups. They had an IA catheter inserted at the end of arthroscopy and only included participants who reported moderate or severe postoperative pain during the first hour after surgery. One of the studies (Solheim 2006) reported 40 of 60 participants (67%) developed moderate to severe pain within one hour. They found that a significantly higher proportion of women (24/26) than men (26/39) reported at least moderate pain (P = 0.018) during the first hour after surgery. The study authors found no difference between IA 5 mg morphine and placebo in pain intensity or pain relief at any time during the 48‐hour observation period and concluded that IA 5 mg morphine did not produce clinically significant pain relief in participants with moderate or severe pain after knee arthroscopy. These controversies originated from the preemptive design of the included articles. Besides, according to Rosseland et al, the incidence of moderate to severe pain after arthroscopy was only 60%. We had to take the participants with mild postoperative pain into account in clinical practice, therefore, we did no test of internal sensitivity, especially when the test may have actually turned out to be biased itself, and just combined data as Gupta et al did.
Of the four dose‐response comparisons, only one was defined as sensitive by Kalso 2002. The result showed that 5 mg of IA morphine provided statistically significantly better analgesia compared with 1 mg of IA morphine. This was confirmed by our meta‐analysis, although the data were quite limited even after all these years of researching.
We believed that a systemic effect of 5 mg IA morphine still had to be considered, particularly in the early period, because no difference could be detected in the efficacy of 5 mg of morphine whether it was injected through IA or IM (Kalso 1997). Additionally, Kalso et al found that 1 mg IA morphine in a 20 ml injection was equivalent to a concentration of about 50 μg/ml. This high concentration would be expected to saturate all the opioid receptors in the knee joint (Kalso 1997). From this point of view, any dose response may be a consequence of systemic effect and residual morphine concentration. The proper dose of IA morphine, and whether this specific dose of morphine is superior to placebo, are still uncertain with the evidence currently available. More trials are needed to make dose‐response comparisons.
Flowchart showing the stepwise screening of search results
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 pain intensity VAS score, outcome: 1.1 1mg morphine vs placebo.
Forest plot of comparison: 1 pain intensity VAS score, outcome: 1.2 1mg morphine vs bupivacaine.
Forest plot of comparison: 1 pain intensity VAS score, outcome: 1.6 1mg morphine vs 5mg morphine.
Comparison 1: Pain intensity VAS score, Outcome 1: 1mg morphine vs placebo
Comparison 1: Pain intensity VAS score, Outcome 2: 1mg morphine vs bupivacaine
Comparison 1: Pain intensity VAS score, Outcome 3: morphine vs NSAIDs
Comparison 1: Pain intensity VAS score, Outcome 4: IA morphine vs IM morphine
Comparison 1: Pain intensity VAS score, Outcome 5: 1mg morphine vs 2mg morphine
Comparison 1: Pain intensity VAS score, Outcome 6: 1mg morphine vs 4mg/5mg morphine
Comparison 2: Analgesia duration, Outcome 1: morphine vs placebo
Comparison 2: Analgesia duration, Outcome 2: morphine vs bupivacaine
Comparison 2: Analgesia duration, Outcome 3: morphine vs NSAIDS
Comparison 2: Analgesia duration, Outcome 4: 1mg morphine vs 2mg morphine
Comparison 2: Analgesia duration, Outcome 5: 1mg morphine vs 5mg morphine
Comparison 3: Adverse events, Outcome 1: morphine vs placebo
Comparison 3: Adverse events, Outcome 2: morphine vs bupivacaine
Comparison 3: Adverse events, Outcome 3: morphine vs NSAIDs
| Morphine compared with placebo for pain control after knee arthroscopy | ||||||
| Patient or population: patients undergoing knee arthroscopy Comparison: placebo (saline) administered via the knee joint | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo | Morphine | |||||
| Pain intensity VAS score | The mean pain score in placebo groups ranged from | The mean pain score in the 1 mg morphine groups was 0.5 cm lower | 297 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score | The mean pain score in placebo groups ranged from | The mean pain score in the 1 mg morphine groups was 0.47 cm lower | 297 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score | The mean pain score in placebo groups ranged from | The mean pain score in the 1 mg morphine groups was 0.88 cm lower | 297 | ⊕⊕⊝⊝ | ||
| Analgesia duration | See comment | See comment | Not estimable | 124 | ⊕⊕⊝⊝ | The data were not pooled. |
| Adverse events | Study population | RR 1.09 | 314 | ⊕⊕⊝⊝ | ||
| 103 per 1000 | 97 per 1000 | |||||
| Moderate | ||||||
| 80 per 1000 | 76 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded one level due to risk of bias: the included studies had small group size and were of low quality. Some studies did not describe randomisation and allocation concealment processes adequately. 2 Downgraded one level due to publication bias: we could not extract usable data for 11 out of 20 studies comparing morphine with placebo. Some studies presented data as figures and not enough data can be used. 3 Downgraded one level due to risk of bias: one of the included studies (Kanbak 1997) was of low quality. 4 Downgraded one level due to publication bias: only three out of 20 studies presented data of analgesic duration. 5 Downgraded one level due to risk of bias: two out of eight studies were of low quality. 6 Downgraded one level due to publication bias: the reported adverse events were not the same. Some only reported the overall incidence of adverse events and some reported a series of adverse events including nausea and vomiting. | ||||||
| Morphine compared with bupivacaine for pain control after knee arthroscopy | ||||||
| Patient or population: patients undergoing knee arthroscopy Comparison: bupivacaine administered via the knee joint | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Bupivacaine | Morphine | |||||
| Pain intensity VAS score | The mean pain score in bupivacaine groups ranged from | The mean pain score in the morphine groups was | 248 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score | The mean pain score in bupivacaine groups ranged from | The mean pain score in the morphine groups was | 330 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score | The mean pain score in bupivacaine groups ranged from | The mean pain score in the morphine groups was | 270 | ⊕⊕⊝⊝ | ||
| Analgesia duration | See comment | See comment | Not estimable | 162 | ⊕⊕⊕⊝ | The data were not pooled. |
| Adverse events | Study population | RR 0.68 (0.09 to 5.17) | 210 | ⊕⊕⊕⊝ | ||
| 76 per 1000 | 49 per 1000 | |||||
| Moderate | ||||||
| 40 per 1000 | 26 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded one level due to risk of bias: the included studies have small group size and are of low quality. Some studies did not describe randomisation and allocation concealment processes adequately. 2 Downgraded one level due to publication bias: six out of 12 studies have exact data for meta‐analysis and others cannot be included in meta‐analysis due to incomplete reporting of outcomes. 3 Downgraded one level due to publication bias: seven out of 12 studies have exact data for meta‐analysis and others cannot be included in meta‐analysis due to incomplete reporting of outcomes. 4 Downgraded one level due to publication bias: five out of 12 studies have exact data for meta‐analysis and others cannot be included in meta‐analysis due to incomplete reporting of outcomes. 5 Downgraded one level due to publication bias: three out of ten studies reported analgesic duration. 6 Downgraded one level due to publication bias: four out of ten studies reported side effects. | ||||||
| Morphine compared with NSAIDs for pain control after knee arthroscopy | ||||||
| Patient or population: patients undergoing knee arthroscopy Comparison: NSAIDs administered via the knee joint | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| NSAIDs | Morphine | |||||
| Pain intensity VAS score | The mean pain score in the NSAIDs groups ranged from | The mean pain score in the morphine groups was | 80 | ⊕⊝⊝⊝ | ||
| Pain intensity VAS score | The mean pain score in the NSAIDs groups ranged from | The mean pain score in the morphine groups was | 80 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score | The mean pain score in the NSAIDs groups ranged from | The mean pain score in the morphine groups was | 80 | ⊕⊕⊝⊝ | ||
| Analgesia duration | See comment | See comment | Not estimable | 50 | ⊕⊕⊝⊝ | The data were not pooled. |
| Adverse events | Study population | RR 0.75 (0.19 to 3.04) | 120 | ⊕⊕⊕⊝ | ||
| 67 per 1000 | 49 per 1000 | |||||
| Moderate | ||||||
| 40 per 1000 | 29 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to risk of bias: one of the included studies (Guler 2002) was of low quality and has potential risk of bias. 2 Downgraded one level due to imprecision: the results showed wide confidence intervals. 3 Downgraded one level due to imprecision: wide confidence intervals. 4 Downgraded one level due to publication bias: three out of ten studies reported analgesic duration. 5 Downgraded one level due to publication bias: only one study reported analgesic duration. 6 Downgraded one level due to risk of bias: one study (Guler 2002) was of low quality. | ||||||
| 1 mg morphine compared with 2 mg/4 mg/5 mg morphine for pain control after knee arthroscopy | ||||||
| Patient or population: patients undergoing knee arthroscopy Comparison: 2 mg/5 mg morphine administered via the knee joint | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| 2 mg / 4 mg/5 mg morphine | 1 mg morphine | |||||
| Pain intensity VAS score 1 mg morphine vs 2 mg morphine | The mean pain score in the 2 mg morphine groups ranged from | The mean pain score in the 1 mg morphine groups was | 105 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score 0‐10 cm VAS score. Scale from: 0 to 10. | The mean pain score in the 2 mg morphine groups ranged from | The mean pain score in the 1 mg morphine groups was | 105 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score 0‐10 cm VAS score. Scale from: 0 to 10. | The mean pain score in the 2 mg morphine groups is 0.45 cm | The mean pain score in the 1 mg morphine groups was | 45 | ⊕⊕⊝⊝ | ||
| Analgesia duration 1 mg morphine vs 2 mg morphine | See comment | See comment | Not estimable | 60 | ⊕⊕⊕⊝ | The data were not pooled. |
| Adverse events 1 mg morphine vs 2 mg morphine | See comment | See comment | Not estimable | None | Not estimable | The were no data available. |
| Pain intensity VAS score 0‐10 cm VAS score. Scale from: 0 to 10. | The mean pain score in the 5 mg morphine groups ranged from | The mean pain score in the1 mg morphine groups was | 67 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score 0‐10 cm VAS score. Scale from: 0 to 10. | The mean pain score in the 5 mg morphine groups ranged from | The mean pain score in the 1 mg morphine groups was | 67 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score 0‐10 cm VAS score. Scale from: 0 to 10. | The mean pain score in the 5mg morphine groups ranged from | The mean pain score in the1mg morphine groups was | 67 | ⊕⊕⊝⊝ | ||
| Analgesia duration 1 mg morphine vs 4 mg/5 mg morphine | See comment | See comment | Not estimable | 24 | ⊕⊕⊕⊝ | The data were not pooled. |
| Adverse events 1 mg morphine vs 4 mg/5 mg morphine | See comment | See comment | Not estimable | None | Not estimable | The were no data available. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to publication bias: one out of three studies only presented data as figures and no usable data were available. 2 Downgraded one level due to imprecision: the results showed wide confidence intervals. 3 Downgraded one level due to publication bias: only one study reported analgesic duration. 4 Downgraded one level due to risk of bias: one of the included studies (Kanbak 1997) was of low quality. 5 Downgraded one level due to imprecision: imprecision arising from the small sample size. 6 Downgraded one level due to publication bias: only one study reported analgesic duration. | ||||||
| IA morphine compared with IM morphine for pain control after knee arthroscopy | ||||||
| Patient or population: patients undergoing knee arthroscopy Comparison: morphine administered intra‐muscularly | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| IM morphine | IA morphine | |||||
| Pain intensity VAS score | The mean pain score in the IM morphine groups ranged from | The mean pain score in the IA morphine groups was | 72 | ⊕⊝⊝⊝ | ||
| Pain intensity VAS score | The mean pain score in the IM morphine groups ranged from | The mean pain score in the IA morphine groups was | 72 | ⊕⊕⊝⊝ | ||
| Pain intensity VAS score | The mean pain score in the IM morphine groups is | The mean pain score in the IA morphine groups was | 39 | ⊕⊕⊝⊝ | ||
| Analgesia duration | See comment | See comment | Not estimable | None | Not estimable | The were no data available. |
| Adverse events | See comment | See comment | Not estimable | None | Not estimable | The were no data available. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to risk of bias: four out of five studies are of low quality. 2 Downgraded one level due to publication bias: only two out of five studies have usable data for meta‐analysis. 3 Downgraded one level due to imprecision: wide confidence intervals. 4 Downgraded one level due to publication bias: only one out of five studies have usable data for meta‐analysis. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 1mg morphine vs placebo Show forest plot | 7 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.1.1 0‐2h | 7 | 297 | Mean Difference (IV, Random, 95% CI) | ‐0.50 [‐1.15, 0.14] |
| 1.1.2 2‐6h | 7 | 297 | Mean Difference (IV, Random, 95% CI) | ‐0.47 [‐1.09, 0.14] |
| 1.1.3 6‐30h | 7 | 297 | Mean Difference (IV, Random, 95% CI) | ‐0.88 [‐1.81, 0.04] |
| 1.2 1mg morphine vs bupivacaine Show forest plot | 6 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.2.1 0‐2h | 5 | 248 | Mean Difference (IV, Random, 95% CI) | 1.43 [0.49, 2.37] |
| 1.2.2 2‐6h | 6 | 330 | Mean Difference (IV, Random, 95% CI) | 0.45 [‐0.47, 1.36] |
| 1.2.3 6‐30h | 5 | 270 | Mean Difference (IV, Random, 95% CI) | ‐0.71 [‐1.23, ‐0.19] |
| 1.3 morphine vs NSAIDs Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.3.1 0‐2h | 2 | 80 | Mean Difference (IV, Random, 95% CI) | 0.95 [‐0.95, 2.85] |
| 1.3.2 2‐6h | 2 | 80 | Mean Difference (IV, Random, 95% CI) | 1.00 [0.12, 1.88] |
| 1.3.3 6‐30h | 2 | 80 | Mean Difference (IV, Random, 95% CI) | 0.43 [‐0.54, 1.39] |
| 1.4 IA morphine vs IM morphine Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.4.1 0‐2h | 2 | 72 | Mean Difference (IV, Fixed, 95% CI) | 0.21 [‐0.48, 0.90] |
| 1.4.2 2‐6h | 2 | 72 | Mean Difference (IV, Fixed, 95% CI) | ‐0.14 [‐0.93, 0.64] |
| 1.4.3 6‐30h | 1 | 39 | Mean Difference (IV, Fixed, 95% CI) | ‐0.30 [‐1.39, 0.79] |
| 1.5 1mg morphine vs 2mg morphine Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.5.1 0‐2h | 2 | 105 | Mean Difference (IV, Random, 95% CI) | ‐0.56 [‐1.93, 0.81] |
| 1.5.2 2‐6h | 2 | 105 | Mean Difference (IV, Random, 95% CI) | ‐0.32 [‐1.69, 1.05] |
| 1.5.3 6‐30h | 1 | 45 | Mean Difference (IV, Random, 95% CI) | 0.55 [‐0.30, 1.40] |
| 1.6 1mg morphine vs 4mg/5mg morphine Show forest plot | 3 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.6.1 0‐2h | 3 | 97 | Mean Difference (IV, Fixed, 95% CI) | 0.46 [‐0.24, 1.16] |
| 1.6.2 2‐6h | 3 | 97 | Mean Difference (IV, Fixed, 95% CI) | 0.44 [‐0.18, 1.05] |
| 1.6.3 6‐30h | 3 | 97 | Mean Difference (IV, Fixed, 95% CI) | 0.67 [0.08, 1.25] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 morphine vs placebo Show forest plot | 3 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2.2 morphine vs bupivacaine Show forest plot | 3 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2.3 morphine vs NSAIDS Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.4 1mg morphine vs 2mg morphine Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.5 1mg morphine vs 5mg morphine Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 morphine vs placebo Show forest plot | 8 | 314 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.09 [0.51, 2.36] |
| 3.2 morphine vs bupivacaine Show forest plot | 4 | 210 | Risk Ratio (M‐H, Random, 95% CI) | 0.68 [0.09, 5.17] |
| 3.3 morphine vs NSAIDs Show forest plot | 3 | 120 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.19, 3.04] |
