Validating speed of onset as a key component of good analgesic response in acute pain.

BACKGROUND: Previous analysis of a single data set in acute pain following third molar extraction demonstrated a strong relationship between the speed of reduction of pain intensity and overall pain relief, as well as need for additional analgesia. METHODS: Individual patient data analysis of a single randomized, double-blind trial of placebo, paracetamol 1000 mg, ibuprofen sodium 400 mg and ibuprofen-poloxamer 400 mg following third molar extraction. Visual analogue scale pain intensity (VASPI) and other measurements were made at baseline, every 5-45 min, and at 60, 90, 120, 180, 240, 300 and 360 min. RESULTS: Most patients produced consistent VASPI results over time. For placebo and paracetamol, few patients achieved low VASPI scores and maintained them. For both ibuprofen formulations, VASPI scores fell rapidly during the first hour and were then typically maintained until later re-medication. Analysis of all patients showed that rapid VASPI reduction in the first hour was strongly correlated with good overall pain relief (high total pain relief over 0-6 h), and with lesser need for additional analgesia within 6 h. Results for this analysis were in very good agreement with a previous analysis, validating the relationship between fast initial pain intensity reduction and overall good pain relief in this setting. CONCLUSIONS: In acute pain following third molar extraction, faster acting analgesic formulations provide earlier onset of pain relief, better overall pain relief and a less frequent need for additional analgesia, indicating longer lasting pain relief.

Overview review: Comparative efficacy of oral ibuprofen and paracetamol (acetaminophen) across acute and chronic pain conditions.

BACKGROUND: Ibuprofen and paracetamol have long been used as analgesics in a range of acute, intermittent and chronic pain conditions. Paracetamol is often the first line analgesic recommended, without consensus about which is the better analgesic. METHODS: An overview review of systematic reviews and meta-analyses directly compares ibuprofen and paracetamol at standard doses in particular painful conditions, or uses indirect comparisons against placebo. Electronic searches for systematic reviews were sought published since 1995 using outcomes approximating to ≥50% pain intensity reduction. Painful conditions were acute post-operative pain, dysmenorrhoea, tension-type headache (TTH), migraine, osteoarthritis and rheumatoid arthritis, back pain, cancer and paediatric pain. There was no systematic assessment of harm. RESULTS: Sixteen systematic reviews and four individual patient data meta-analyses were included. Ibuprofen was consistently superior to paracetamol at conventional doses in a range of painful conditions. Two direct comparisons favoured ibuprofen (acute pain, osteoarthritis). Three of four indirect comparisons favoured ibuprofen (acute pain, migraine, osteoarthritis); one showed no difference (TTH), although there were methodological problems. In five pain conditions (dysmenorrhoea, paediatric pain, cancer pain, back pain and rheumatoid arthritis), there were limited data on paracetamol and ibuprofen. CONCLUSIONS: At standard doses in different painful conditions, ibuprofen was usually superior producing more patients with the degree of pain relief that patients feel worthwhile. Neither of the drugs will be effective for everyone, and both are needed. This overview questions the practice of routinely using paracetamol as a first line analgesic because there is no good evidence for efficacy of paracetamol in many pain conditions.

Challenges in design and interpretation of chronic pain trials.

The process of systematic review has shone a light on the methodology of randomized controlled trials. Notably, a range of potential biases hinders the interpretation of chronic pain trials. These include a consistent bias favouring active over placebo in trials that are small and of short duration. The use of the 'last observation carried forward' imputation method is known to inflate results, often generating statistically significance when adverse event withdrawals are high; in clinical practice terms, this is the wrong answer. Patients want outcomes of low pain scores, large reductions in pain and relief from associated symptoms, with improvements in ability to function and in quality of life. Some patients achieve this, but many do not. The distribution of benefit is skewed and the use of average pain scores, or change in pain, can be misleading compared with responder analysis in which withdrawal is regarded as non-response. Historically, chronic pain trials have had a simple classic or a crossover design. They have been small and short, and used inappropriate imputation and outcomes unconnected to the experiences of most patients. While these designs are useful for answering some questions, they may be insensitive for many interventions. Newer designs, like enriched enrolment randomized withdrawal (EERW) trials or clinical effectiveness trials, are potentially more interesting and informative.

Relative efficacy of oral analgesics after third molar extraction--a 2011 update.

This article provides a summary of the efficacy, and relative efficacy, of 38 different drugs or drug combinations tested in standard postoperative pain trials. It will help clinicians and patients make informed choices about analgesia based on pain relief, duration of action, and adverse events, which can then be put into context for the individual patient, depending on local availability. This article highlights the fact that no single drug is effective in all patients--even the best drugs fail to provide good levels of pain relief in at least 30%. These patients should try a different analgesic.

Oral morphine for cancer pain.

BACKGROUND: This is an updated version of a previous Cochrane review first published in Issue 4, 2003 of The Cochrane Library. Morphine has been used for many years to relieve pain. Oral morphine in either immediate release or modified release form remains the analgesic of choice for moderate or severe cancer pain. OBJECTIVES: To determine the efficacy of oral morphine in relieving cancer pain and to assess the incidence and severity of adverse effects. SEARCH STRATEGY: The following databases were searched: Cochrane Pain, Palliative and Supportive Care Group Trials Register (December 2006); Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2006, Issue 4); MEDLINE (1966 to December 2006); and EMBASE (1974 to December 2006). SELECTION CRITERIA: Published randomised controlled trials (RCTs) reporting on the analgesic effect of oral morphine in adults and children with cancer pain. Any comparator trials were considered. Trials with fewer than ten participants were excluded. DATA COLLECTION AND ANALYSIS: One review author extracted data, which was checked by the other review author. There were insufficient comparable data for meta-analysis to be undertaken or to produce numbers-needed-to-treat (NNT) for the analgesic effect. MAIN RESULTS: In this update, nine new studies with 688 participants were added. Fifty-four studies (3749 participants) met the inclusion criteria. Fifteen studies compared oral modified release morphine (Mm/r) preparations with immediate release morphine (MIR). Twelve studies compared Mm/r in different strengths, five of these included 24-hour modified release products. Thirteen studies compared Mm/r with other opioids. Six studies compared MIR with other opioids. Two studies compared oral Mm/r with rectal Mm/r. Two studies compared MIR with MIR by a different route of administration. One study was found comparing each of the following: Mm/r tablet with Mm/r suspension; Mm/r with non-opioids; MIR with non-opioids; and oral morphine with epidural morphine. Morphine was shown to be an effective analgesic. Pain relief did not differ between Mm/r and MIR. Modified release versions of morphine were effective for 12 or 24-hour dosing depending on the formulation. Daily doses in studies ranged from 25 mg to 2000 mg with an average of between 100 mg and 250 mg. Dose titration were undertaken with both instant release and modified release products. Adverse effects were common but only 4% of patients discontinued treatment because of intolerable adverse effects. AUTHORS' CONCLUSIONS: The randomised trial literature for morphine is small given the importance of this medicine. Most trials recruited fewer than 100 participants and did not provide appropriate data for meta-analysis. Trial design was frequently based on titration of morphine or comparator to achieve adequate analgesia, then crossing participants over in crossover design studies. It was not clear if these trials are sufficiently powered to detect any clinical differences between formulations or comparator drugs. Studies added to the review reinforce the view that it is possible to use modified release morphine to titrate to analgesic effect. There is qualitative evidence for effectiveness of oral morphine which compares well to other available opioids. There is limited evidence to suggest that transmucosal fentanyl provides more rapid pain relief for breakthrough pain compared to morphine.

Antidepressants for neuropathic pain.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 3, 2005 of The Cochrane Library. For many years antidepressant drugs have been used to manage neuropathic pain, and are often the first choice treatment. It is not clear, however, which antidepressant is more effective, what role the newer antidepressants can play in treating neuropathic pain, and what adverse effects are experienced by patients. OBJECTIVES: To determine the analgesic effectiveness and safety of antidepressant drugs in neuropathic pain. SEARCH STRATEGY: Randomised controlled trials (RCTs) of antidepressants in neuropathic pain were identified in MEDLINE (1966 to Oct 2005); EMBASE (1980 to Oct 2005); the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, Issue 3, 2005; and the Cochrane Pain, Palliative and Supportive Care Trials Register (May 2002). Additional reports were identified from the reference list of the retrieved papers, and by contacting investigators. SELECTION CRITERIA: RCTs reporting the analgesic effects of antidepressant drugs in adult patients, with subjective assessment of pain of neuropathic origin. Studies that included patients with chronic headache and migraine were excluded. DATA COLLECTION AND ANALYSIS: Two review authors agreed the included studies, extracted data, and assessed methodological quality independently. Sixty one trials of 20 antidepressants were considered eligible (3293 participants) for inclusion. Relative Risk (RR) and Number-Needed-to-Treat (NNTs) were calculated from dichotomous data for effectiveness and adverse effects. This update includes 11 additional studies (778 participants). MAIN RESULTS: Sixty one RCTs were included in total. Tricyclic antidepressants (TCAs) are effective and have an NNT of 3.6 (95% CI 3 to 4.5) RR 2.1 (95% CI 1.8 to 2.5) for the achievement of at least moderate pain relief. There is limited evidence for the effectiveness of the newer SSRIs but no studies of SNRIs were found. Venlafaxine (three studies) has an NNT of 3.1 (95% CI 2.2 to 5.1) RR 2.2 (95% CI 1.5 to 3.1). There were insufficient data to assess effectiveness for other antidepressants such as St Johns Wort and L-tryptophan. For diabetic neuropathy the NNT for effectiveness was 1.3 (95% CI 1.2 to 1.5) RR 12.4 (95% CI 5.2 to 29.2) (five studies); for postherpetic neuralgia 2.7 (95% CI 2 to 4.1), RR 2.2 (95% CI 1.6 to 3.1) (four studies). There was evidence that TCAs are not effective in HIV-related neuropathies. The number needed to harm (NNH) for major adverse effects defined as an event leading to withdrawal from a study was 28 (95% CI 17.6 to 68.9) for amitriptyline and 16.2 (95% CI 8 to 436) for venlafaxine. The NNH for minor adverse effects was 6 (95% CI 4.2 to 10.7) for amitriptyline and 9.6 (95% CI 3.5 to 13) for venlafaxine. AUTHORS' CONCLUSIONS: This update has provided additional confirmation on the effectiveness of antidepressants for neuropathic pain and has provided new information on another antidepressant - venlafaxine. There is still limited evidence for the role of SSRIs. Whether antidepressants prevent the development of neuropathic pain (pre-emptive use) is still unclear. Both TCAs and venlafaxine have NNTs of approximately three. This means that for approximately every three patients with neuropathic pain who are treated with either of these antidepressants, one will get at least moderate pain relief. There is evidence to suggest that other antidepressants may be effective but numbers of participants are insufficient to calculate robust NNTs. SSRIs are generally better tolerated by patients and more high quality studies are required.

Lamotrigine for acute and chronic pain.

BACKGROUND: Anticonvulsant medicines have a place in the treatment of neuropathic pain (pain due to nerve damage). This review looks at the evidence for the pain relieving properties of lamotrigine. OBJECTIVES: To assess the analgesic efficacy and adverse effects of the anticonvulsant lamotrigine for acute and chronic pain. SEARCH STRATEGY: Randomised Controlled Trials (RCTs) of lamotrigine (and key brand names Lamictal, Lamictin, Neurium) in acute, chronic or cancer pain were identified from MEDLINE (1966 to August 2006), EMBASE 1994 to August 2006 and the CENTRAL register on The Cochrane Library (Issue 3, 2006). Additional reports were sought from the reference list of the retrieved papers. SELECTION CRITERIA: RCTs investigating the use of lamotrigine (any dose and by any route) for treatment of acute or chronic pain. Assessment of pain intensity or pain relief, or both, using validated scales. Participants were adults aged 18 and over. Only full journal publication articles were included. DATA COLLECTION AND ANALYSIS: Dichotomous data were used to calculate relative risk with 95% confidence intervals using a fixed effects model unless significant statistical heterogeneity was found. Continuous data was also reported where available. Meta-analysis was undertaken using a fixed effect model unless significant heterogeneity was present (I(2) >50%) in which case a random effects model was used. Numbers-needed-to-treat (NNTs) were calculated as the reciprocal of the absolute risk reduction. For unwanted effects, the NNT becomes the number-needed-to-harm (NNH) and was calculated. MAIN RESULTS: Sixteen studies were identified. Nine studies were excluded. No studies for acute pain were identified. The seven included studies involved 502 participants, all for neuropathic pain. The studies covered the following conditions: central post stroke pain (1), diabetic neuropathy (1), HIV related neuropathy (2), intractable neuropathic pain (1), spinal cord injury related pain (1) and trigeminal neuralgia (1). The studies included participants in the age range of 26 to 77 years. Only one study for HIV related neuropathy had a statistically significant result for a sub group of patients on anti-retroviral therapy; this result is unlikely to be clinically significant NNT 4.3 (95% CI 2.3 to 37). Approximately 7% of participants taking lamotrigine reported a skin rash. AUTHORS' CONCLUSIONS: Given the availability of more effective treatments including anticonvulsants and antidepressant medicines, lamotrigine does not have a significant place in therapy at present. The limited evidence currently available suggests that lamotrigine is unlikely to be of benefit for the treatment of neuropathic pain.

The ORION statement: guidelines for transparent reporting of outbreak reports and intervention studies of nosocomial infection.

The quality of research in hospital epidemiology (infection control) must be improved to be robust enough to influence policy and practice. In order to raise the standards of research and publication, a CONSORT equivalent for these largely quasi-experimental studies has been prepared by the authors of two relevant systematic reviews, following consultation with learned societies, editors of journals and researchers. It consists of a 22 item checklist, and a summary table. The emphasis is on transparency to improve the quality of reporting and on the use of appropriate statistical techniques. The statement has been endorsed by a number of professional special interest groups and societies. Like CONSORT, ORION should be considered a 'work in progress', which requires ongoing dialogue for successful promotion and dissemination. The statement is therefore offered for further public discussion. Journals and research councils are strongly recommended to incorporate it into their submission and reviewing processes. Feedback to the authors is encouraged and the statement will be revised in 2 years.

Carbamazepine for acute and chronic pain.

BACKGROUND: Anticonvulsant drugs have been used in the management of pain since the 1960s. The clinical impression is that they are useful for chronic neuropathic pain, especially when the pain is lancinating or burning. OBJECTIVES: To evaluate the analgesic effectiveness and adverse effects of the anticonvulsant medicine carbamazepine for pain management in clinical practice and to identify a clinical research agenda. Migraine and headache studies are not included in this review. SEARCH STRATEGY: Randomised trials (RCTs) of anticonvulsants in acute, chronic or cancer pain were identified by MEDLINE (1966-2004), EMBASE (1994-2004), SIGLE (1980-2004) and the Cochrane Controlled Trials Register (CENTRAL/CCTR) (Cochrane Library Issue 3, 2003). In addition, 41 medical journals were hand searched for a previous version of this review. Additional reports were identified from the reference list of the retrieved papers, and by contacting investigators. Date of most recent search: November 2004. SELECTION CRITERIA: Randomised trials reporting the analgesic effects of carbamazepine in patients, with subjective pain assessment as either the primary or a secondary outcome. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers, and trials were quality scored. Numbers-needed-to-treat (NNTs) were calculated from dichotomous data for effectiveness, adverse effects and drug-related study withdrawal, for individual studies and for pooled data. MAIN RESULTS: Twelve studies were included (404 participants). Four studies included trigeminal neuralgia patients. Two studies which provided evaluable data yielded an NNT for effectiveness of 1.8 (95%CI 1.4-2.8). For diabetic neuropathy there was insufficient data for an NNT to be calculated.Numbers-needed-to-harm (NNHs) were calculated where possible by combining studies for each drug entity irrespective of the condition treated. The results were, for minor harm, carbamazepine 3.7 (CI 2.4-7.8), NNHs for major harm were not statistically significant for carbamazepine compared with placebo. There is no evidence that carbamazepine is effective for acute pain. AUTHORS' CONCLUSIONS: There is evidence to show that carbamazepine is effective but trials are small.

Gabapentin for acute and chronic pain.

BACKGROUND: Anticonvulsant drugs have been used in the management of pain since the 1960s. The clinical impression is that they are useful for chronic neuropathic pain, especially when the pain is lancinating or burning. OBJECTIVES: To evaluate the analgesic effectiveness and adverse effects of gabapentin for pain management in clinical practice. SEARCH STRATEGY: Randomised trials of gabapentin in acute, chronic or cancer pain were identified by MEDLINE (1966-Nov 2004), EMBASE (1994-Nov 2004), SIGLE (1980-Jan 2004) and the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library Issue 4, 2004). Additional reports were identified from the reference list of the retrieved papers, and by contacting investigators. Date of most recent search: January 2004. SELECTION CRITERIA: Randomised trials reporting the analgesic effects of gabapentin in patients, with subjective pain assessment as either the primary or a secondary outcome. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers, and trials were quality scored. Numbers-needed-to-treat (NNTs) were calculated, where possible, from dichotomous data for effectiveness, adverse effects and drug-related study withdrawal. MAIN RESULTS: Fourteen reports describing 15 studies of gabapentin were considered eligible (1468 participants). One was a study of acute pain. The remainder included the following conditions: post-herpetic neuralgia (two studies), diabetic neuropathy (seven studies), a cancer related neuropathic pain (one study) phantom limb pain (one study), Guillain Barré syndrome (one study) , spinal chord injury pain (one study) and various neuropathic pains (one study). The study in acute post-operative pain (70 participants) showed no benefit for gabapentin compared to placebo for pain at rest. In chronic pain, the NNT for improvement in all trials with evaluable data is 4.3 (95%CI 3.5-5.7). Forty two percent of participants improved on gabapentin compared to 19% on placebo. The number needed to harm(NNH) for adverse events leading to withdrawal from a trial was not significant. Fourteen percent of participants withdrew from active arms compared to 10% in placebo arms. The NNH for minor harm was 3.7 (95% CI 2.4 to 5.4). The NNT for effective pain relief in diabetic neuropathy was 2.9 (95% CI 2.2 to 4.3) and for post herpetic neuralgia 3.9 (95% CI 3 to 5.7). AUTHORS' CONCLUSIONS: There is evidence to show that gabapentin is effective in neuropathic pain. There is limited evidence to show that gabapentin is ineffective in acute pain.

Antidepressants for neuropathic pain.

BACKGROUND: For many years antidepressant drugs have been used to manage neuropathic pain, and are often the first choice treatment. It is not clear, however, which antidepressant is more effective, what role the newer antidepressants can play in treating neuropathic pain, and what adverse effects are experienced by patients. OBJECTIVES: To determine the analgesic effectiveness and safety of antidepressant drugs in neuropathic pain. Migraine and headache studies were not considered. SEARCH STRATEGY: Randomised trials of antidepressants in neuropathic pain were identified in MEDLINE (1966 to Dec 2003); EMBASE (1980 to Dec 2003); the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library 2004, Issue 1; and the Cochrane Pain, Palliative and Supportive Care Trials Register (May 2002). Additional reports were identified from the reference list of the retrieved papers, and by contacting investigators. SELECTION CRITERIA: Randomised trials reporting the analgesic effects of antidepressant drugs in adult patients, with subjective assessment of pain of neuropathic origin. Studies that included patients with chronic headache and migraine were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers agreed the included studies, extracted data, and assessed methodological quality independently. Fifty trials of 19 antidepressants were considered eligible (2515 patients) for inclusion. Relative Risk (RR) estimates and Number-Needed-to-Treat (NNTs) were calculated from dichotomous data for effectiveness and adverse effects. MAIN RESULTS: Tricyclic antidepressants (TCAs) are effective treatments for the treatment of neuropathic pain. Amitriptyline has an NNT of 2 (95%CI 1.7 to 2.5) RR 4.1(95%CI 2.9-5.9) for the achievement of at least moderate pain relief. There is limited evidence for the effectiveness of the newer selective serotonin reuptake inhibitor antidepressant drugs (SSRIs). There were insufficient data for an assessment of evidence of effectiveness for other antidepressants such as St Johns Wort, venlafaxine and L-tryptophan. For diabetic neuropathy the NNT for effectiveness was 1.3 (95%CI 1.2 to 1.5) RR 12.4(95%CI 5.2-29.2) (five studies); for postherpetic neuralgia 2.2 (95%CI 1.7 to 3.1), RR 4.8(95%CI 2.5-9.5)(three studies). There was evidence that TCAs are not effective in HIV-related neuropathies. The number needed to harm(NNH) for major adverse effects defined as an event leading to withdrawal from a study was 16 (95%CI: 10-45). The NNH for minor adverse effects was 4.6 (95%CI 3.3-6.7) AUTHORS' CONCLUSIONS: Antidepressants are effective for a variety of neuropathic pains. The best evidence available is for amitriptyline. There are only limited data for the effectiveness of SSRIs. It is not possible to identify the most effective antidepressant until more studies of SSRIs are conducted.

Relative efficacy of oral analgesics after third molar extraction.

OBJECTIVES: To compare the relative efficacy of analgesics after third molar extraction from systematic reviews of randomised, double blind studies. DATA SOURCES: Dental trials from systematic reviews of randomised, double-blind studies of analgesics in acute pain. DATA SELECTION: Number of patients with moderate or severe pain achieving at least half pain relief over 4 to 6 hours after a single oral dose of analgesic. DATA EXTRACTION: Independently by two reviewers. DATA SYNTHESIS: Use of dichotomous information from active and placebo treatments, first to calculate the statistical significance using relative risk, and then to evaluate the clinical relevance using number needed to treat (NNT). Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase-2 (COX-2) inhibitors had the lowest (best) NNTs for the outcome of at least half pain relief over 4-6 hours compared with placebo. With the best performing analgesics, 50-70 patients out of 100 had good pain relief compared with about 10 out of 100 with placebo. Only paracetamol 600/650 mg plus codeine 60 mg was associated with any significant increase in any patient experiencing an adverse event. CONCLUSIONS: NSAIDs and COX-2 inhibitors have the lowest (best) NNTs. They may also have fewer adverse effects after third molar surgery, though conclusive evidence is lacking. At least 80% of analgesic prescribing by UK dentists is in line with the best available evidence on efficacy and safety.

Oral morphine for cancer pain.

BACKGROUND: Morphine has been used to relieve pain for many years. Oral morphine in either immediate release or sustained release form remains the analgesic of choice for moderate or severe cancer pain. OBJECTIVES: To determine the efficacy of oral morphine in relieving cancer pain. To assess the incidence and severity of adverse effects. SEARCH STRATEGY: The following databases were searched: The Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Library, Issue 4, 2002; the trials register of the Cochrane Pain, Palliative and Supportive Care group (February 2002); MEDLINE 1966 to December 2002; EMBASE 1988 to December 2002; and the Oxford Pain Relief database 1950 to 1994. SELECTION CRITERIA: Published randomised controlled trials (full reports) reporting on the analgesic effect of oral morphine in adults and children with cancer pain. Any comparator trials were considered. Trials with fewer than 10 subjects were excluded. DATA COLLECTION AND ANALYSIS: One reviewer extracted data, and the findings were checked by two other reviewers. There were insufficient comparable data for meta-analysis to be undertaken, or to produce numbers-needed-to-treat (NNT) for the analgesic effect. MAIN RESULTS: Forty five studies (3061 subjects) met the inclusion criteria. Fourteen studies compared oral sustained release morphine (MSR) preparations with immediate release morphine (MIR). Eight studies compared MSR and MSR in different strengths. Nine studies compared MSR with other opioids. Five studies compared MIR with other opioids. Two studies compared oral MSR with rectal MSR. One study was found comparing each of the following: MSR tablet with MSR suspension; MSR with MSR at different dose frequencies; MSR with non-opioids; MIR with non-opioids; oral morphine with epidural morphine; and MIR with MIR by a different route of administration. Morphine was shown to be an effective analgesic. Pain relief did not differ between MSR and MIR. Sustained release versions of morphine were effective for 12 or 24 hour dosing depending on the formulation. Adverse effects were common but only 4% of patients discontinued treatment because of intolerable adverse effects. REVIEWER'S CONCLUSIONS: The randomised trial literature for morphine is small given the importance of this medicine. Most trials recruited fewer than 100 participants, and did not provide appropriate data for meta-analysis. Trial design was frequently based on titration of morphine or comparator to achieve adequate analgesia, then crossing subjects over in crossover design studies. It is not clear if these trials are sufficiently powered to detect any clinical differences between formulations or comparator drugs.

Bisphosphonates for the relief of pain secondary to bone metastases.

BACKGROUND: Bisphosphonates form part of standard therapy for hypercalcemia and the prevention of skeletal events in some cancers. However, the role of bisphosphonates in pain relief for bony metastases remains uncertain. OBJECTIVES: To determine the effectiveness of bisphosphonates for the relief of pain from bone metastases. SEARCH STRATEGY: MEDLINE (1966-1999), EMBASE (1980-1999), CancerLit (1966-1999), the Cochrane library (Issue 1, 2000) and the Oxford Pain Database were searched using the strategy devised by the Cochrane Pain, Palliative and Supportive Care Group with additional terms 'diphosphonate', 'bisphosphonate', 'multiple myeloma' and 'bone neoplasms'. (Last search: January 2000). SELECTION CRITERIA: Randomized trials of bisphosphonates compared with open, blinded, or different doses/types of bisphosphonates in cancer patients were included where pain and/or analgesic consumption were outcome measures. Studies where pain was reported only by observers were excluded. DATA COLLECTION AND ANALYSIS: Article eligibility, quality assessment and data extraction were undertaken by both reviewers. The proportions of patients with pain relief at 4, 8 and 12 weeks were assessed. The proportion of patients with analgesic reduction, the mean pain score, mean analgesic consumption, adverse drug reactions, and quality of life data were compared as secondary outcomes. MAIN RESULTS: Thirty randomized controlled studies (21 blinded, four open and five active control) with a total of 3682 subjects were included. For each outcome, there were few studies with available data. For the proportion of patients with pain relief (eight studies) pooled data showed benefits for the treatment group, with an NNT at 4 weeks of 11[95% CI 6-36] and at 12 weeks of 7 [95% CI 5-12]. In terms of adverse drug reactions, the NNH was 16 [95% CI 12-27] for discontinuation of therapy. Nausea and vomiting were reported in 24 studies with a non-significant trend for greater risk in the treatment group. One study showed a small improvement in quality of life for the treatment group at 4 weeks. The small number of studies in each subgroup with relevant data limited our ability to explore the most effective bisphosphonates and their relative effectiveness for different primary neoplasms. REVIEWER'S CONCLUSIONS: There is evidence to support the effectiveness of bisphosphonates in providing some pain relief for bone metastases. There is insufficient evidence to recommend bisphosphonates for immediate effect; as first line therapy; to define the most effective bisphosphonates or their relative effectiveness for different primary neoplasms. Bisphosphonates should be considered where analgesics and/or radiotherapy are inadequate for the management of painful bone metastases.

Encouraging good antimicrobial prescribing practice: a review of antibiotic prescribing policies used in the South East Region of England.

BACKGROUND: Good prescribing practice has an important part to play in the fight against antimicrobial resistance. Whilst it was perceived that most hospitals and Health Authorities possessed an antibiotic policy, a review of antibiotic policies was conducted to gain an understanding of the extent, quality and usefulness of these policies. METHODS: Letters were sent to pharmacists in hospitals and health authorities in across the South East region of the National Health Service Executive (NHSE) requesting antibiotic policies. data were extracted from the policies to assess four areas; antibiotic specific, condition specific, patient specific issues and underpinning evidence. RESULTS: Of a possible 41 hospital trusts and 14 health authorities, 33 trusts and 9 health authorities (HAs) provided policies. Both trust and HA policies had a median publication date of 1998 (trust range 1993-99, HA 1994-99). Eleven policies were undated. The majority of policies had no supporting references for the statements made. All policies provided some details on specific antibiotics. Gentamicin and ciprofloxacin were the preferred aminoglycoside and quinolone respectively with cephalosporins being represented by cefuroxime or cefotaxime in trusts and cephradine or cephalexin in HAs. 26 trusts provided advice on surgical prophylaxis, 17 had meningococcal prophylaxis policies and 11 covered methicillin resistant Staphylococcus aureus (MRSA). There was little information for certain groups such as neonates or children, the pregnant or the elderly. CONCLUSION: There was considerable variation in content and quality across policies, a clear lack of an evidence base and a need to revise policies in line with current recommendations.

Are the pneumococcal polysaccharide vaccines effective? Meta-analysis of the prospective trials.

The objective was to review the evidence of effectiveness of the polyvalent polysaccharide pneumococcal vaccine from prospective properly randomised controlled trials comparing pneumococcal vaccines with placebo in subjects who are immunocompetent and those likely to have an impaired immune system. Databases searched included the Cochrane Library, (issue 2, 2000), MEDLINE (1966-August 2000), PubMed (to August 2000) and EMBASE ( to August 2000). Reference lists of reports and reviews were also searched. To be included in the analysis, a study had to have been a prospective randomised comparison of a polysaccharide pneumococcal vaccine (any valency) and to have a placebo or no treatment comparison group. Papers had to report important clinical outcomes, such as rates of pneumonia, pneumococcal pneumonia, lower respiratory tract infections, pneumonia deaths or bacteraemia. Serological outcomes were not sought. Thirteen randomised comparisons with over 45,000 subjects were identified in an extensive literature review. Eight studies had a quality score of 3 or more on a scale of 1 to 5. In three comparisons with 21,152 immunocompetent subjects (South African gold miners, New Guinea highlanders) pneumococcal vaccination was effective in reducing the incidence of all-cause pneumonia (relative risk 0.56, 95% confidence interval 0.47 to 0.66), pneumococcal pneumonia (0.16; 0.11 to 0.23), pneumonia deaths (0.70; 0.50 to 0.96) and bacteraemia (0.18; 0.09 to 0.34). In ten comparisons in over 24,000 people who were elderly or likely to have impaired immune systems, pneumococcal vaccination was without effect for any outcome. Present guidelines recommend pneumococcal vaccination for "high-risk" groups. There is no evidence from randomised trials that this is of any benefit.

Single dose oral ibuprofen and diclofenac for postoperative pain.

BACKGROUND: Ibuprofen and diclofenac are two widely used non-steroidal anti-inflammatory (NSAID) analgesics. It is therefore important to know which drug should be recommended for postoperative pain relief. This review seeks to compare the relative efficacy of the two drugs, and also considers the issues of safety and cost. OBJECTIVES: To assess the analgesic efficacy of ibuprofen and diclofenac in single oral doses for moderate to severe postoperative pain. SEARCH STRATEGY: Randomised trials were identified by searching Medline (1966 to December 1996), Embase (1980 to January 1997), the Cochrane Library (Issue 3 1996), Biological Abstracts (January 1985 to December 1996) and the Oxford Pain Relief Database (1950 to 1994). Date of the most recent searches: July 1998. SELECTION CRITERIA: The inclusion criteria used were: full journal publication, postoperative pain, postoperative oral administration, adult patients, baseline pain of moderate to severe intensity, double-blind design, and random allocation to treatment groups which compared either ibuprofen or diclofenac with placebo. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers, and trials were quality scored. Summed pain relief or pain intensity difference over four to six hours was extracted, and converted into dichotomous information yielding the number of patients with at least 50% pain relief. This was then used to calculate the relative benefit and the number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief. MAIN RESULTS: Thirty-four trials compared ibuprofen and placebo (3,591 patients), six compared diclofenac with placebo (840 patients) and there were two direct comparisons of diclofenac 50 mg and ibuprofen 400 mg (130 patients). In postoperative pain the NNTs for ibuprofen 200 mg were 3.3 (95% confidence interval 2.8 to 4.0) compared with placebo, for ibuprofen 400 mg 2.7 (2.5 to 3.0), for ibuprofen 600 mg 2.4 (1.9 to 3.3), for diclofenac 50 mg 2.3 (2.0 to 2.7) and for diclofenac 100 mg 1.8 (1.5 to 2.1). Direct comparisons of diclofenac 50 mg with ibuprofen 400 mg showed no significant difference between the two. REVIEWER'S CONCLUSIONS: Both drugs work well. Choosing between them is an issue of dose, safety and cost.

Single dose oral aspirin for acute pain.

BACKGROUND: Aspirin has been known to be an effective analgesic for many years and is commonly used throughout the world for many different pain conditions. It is important for both prescribers and patients to have the best possible information about the efficacy and safety of analgesics, and this need is reflected in patient surveys which show that postoperative pain is often poorly managed. We also need to benchmark relative efficacy and safety of current analgesics so that we can compare them with new analgesics. OBJECTIVES: To quantitatively assess the analgesic efficacy and adverse effects of a single-dose of aspirin in acute pain of moderate to severe intensity. SEARCH STRATEGY: Randomised trials were identified by searching Medline (1966 to March 1998), Embase (1980 to January 1998), the Cochrane Library (Issue 1,1998) and the Oxford Pain Relief Database (1950 to 1994). SELECTION CRITERIA: The inclusion criteria used were: full journal publication, postoperative pain or a mixture of postoperative and acute trauma pain, oral administration, adult patients, baseline pain of moderate to severe intensity, double-blind design, and random allocation to treatment groups which compared aspirin with placebo. DATA COLLECTION AND ANALYSIS: Summed pain relief or pain intensity difference over four to six hours was extracted, and converted into dichotomous information yielding the number of patients with at least 50% pain relief. This was then used to calculate the relative benefit and the number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief. MAIN RESULTS: Seventy-two randomised single-dose trials met our inclusion criteria, with 3253 patients given aspirin, and 3297 placebo. Significant benefit of aspirin over placebo was shown for aspirin 600/650 mg, 1000 mg and 1200 mg, NNTs for at least 50% pain relief of 4.4 (4.0 to 4.9), 4.0 (3.2 to 5.4) and 2.4 (1.9 to 3.2) respectively. Single-dose aspirin 600/650 mg produced significantly more drowsiness and gastric irritation than placebo, with a number-needed-to-harm (NNH) of 28 (19 to 52) and 38 (22 to 174) respectively. Type of pain model, pain measurement, sample size, quality of study design, and study duration had no significant impact on the results. REVIEWER'S CONCLUSIONS: Aspirin is an effective analgesic for acute pain of moderate to severe intensity with a clear dose-response. Drowsiness and gastric irritation were seen as significant adverse effects even though the studies were single-dose. The pain relief achieved with aspirin was very similar milligram for milligram to that seen with paracetamol.