St Peter's Hospital, Chertsey, Surrey and
1 University of Nottingham, Nottingham, UK
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Abstract |
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Methods. Eighty patients with OA of the knee were recruited from a rheumatology out-patient clinic and received either glucosamine sulphate 1500 mg daily for 6 months or dummy placebo. The primary outcome measure was patients' global assessment of pain in the affected knee.
Results. Area under the curve analysis for the primary outcome measure showed no difference between placebo and glucosamine [mean difference 0.15 mm, 95% confidence interval (CI) -8.78 to 9.07]. The placebo response was 33%. There was a statistically significant difference between groups in knee flexion (mean difference 13°, 95% CI -23.13 to -1.97), but this difference was small and could have been due to measurement error.
Conclusions. As a symptom modifier in OA patients with a wide range of pain severities, glucosamine sulphate was no more effective than placebo.
KEY WORDS: Osteoarthritis, Glucosamine sulphate, Analgesia, Complementary therapy, Nutritional supplement, Pain.
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Introduction |
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In this paper we report the results of a pragmatic, randomized, placebo-controlled, trial of glucosamine sulphate for the treatment of pain in knee OA in UK patients.
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Patients and methods |
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Interventions
Intervention group.
Glucosamine sulphate 1500 mg was taken as 500 mg capsules three times daily for 6 months. Glucosamine sulphate capsules manufactured by Health Perception UK contain 500 mg of potassium chloride-free glucosamine sulphate, 300 mg of vitamin C, 300 mg of calcium carbonate and 5 mg of manganese.
Placebo control group.
Dummy placebo capsules containing calcium carbonate were taken three times daily for 6 months. The dummy placebo capsules were also manufactured by Health Perception UK specifically for the purposes of this study to ensure the placebo was a true dummy for the active glucosamine sulphate.
All participants were permitted to continue their existing non-steroidal anti-inflammatory drug (NSAID) medication and encouraged to avoid changing their dose or medication during the course of the study. Use of NSAIDs was recorded at each follow-up assessment. The patients were allowed access to paracetamol or other proprietary or prescribed simple analgesia and reported use of analgesia was collected using a patient diary and recorded at each follow-up assessment. Adherence to trial medication was assessed using a returned capsule count at each follow-up visit.
Outcome measurement and follow-up
The patients were assessed four times during the study period, at 0, 6, 12 and 24 weeks. At each visit vital signs were recorded (pulse, blood pressure, weight) and blood and urine were tested according to protocol at 0 and 24 weeks (full blood count, liver and kidney function tests and urinalysis by stick testing). Outcome measures were collected at each visit. Four 100 mm visual analogue scales (VAS) were used to measure pain in the affected knee at rest, on movement and the patient's overall assessment of pain and stiffness. VAS are scored from 0 to 100, where 0 indicates no pain and 100 is the worst pain imaginable. The primary outcome measure was the VAS overall assessment of pain in the affected knee. The WOMAC Osteoarthritis Index [9] was used to evaluate functional activity and the McGill pain questionnaire [10] assessed the affective and sensory components of pain. The functional subscale of the WOMAC produces a range of scores from 0 to 68, where 0 indicates no functional disability and 68 indicates extreme difficulty performing daily living tasks. The pain and stiffness subscales of the WOMAC have scores of 020 and 08, respectively, with 0 representing no pain or stiffness. Similarly, high scores on the McGill pain questionnaire indicate more pain.
All outcome measures are well validated and have been used extensively in clinical trials in rheumatology. The VAS pain scales, the WOMAC questionnaire and the McGill pain questionnaire were self-administered by the patients.
The range of movement of the knees in flexion and extension was measured using a long arm goniometer following a standardized method recommended for knee OA [11]. In this method, the patient was examined lying down and all measurements were taken from the lateral aspect of the knee using only active movements. The central pivot of the goniometer was placed over the midpoint of the lateral joint margin with the upper arm of the goniometer aligned with the greater trochanter and the lower arm with the lateral malleolus. The neutral position was taken as zero unless the knee was hyperextended (when a minus value was recorded) or flexed (when a positive value was recorded). The patient was then asked to extend and flex their knee to its limit and readings were taken from the goniometer. This method has intra- and inter-rater reliability coefficients of 0.890.91.
Use of rescue analgesia and adherence to trial medication were recorded at each follow-up assessment. Adverse events, patient withdrawals and concomitant illnesses were recorded in accordance with good clinical practice guidelines. The same research nurse, blind to the patients' treatment allocations, made all study measurements on each patient at every visit.
Study power
Power calculations based on published data for patients with OA indicated that 38 patients were required in each treatment group to detect a 20 mm difference in VAS overall pain score with 90% power at 1% significance (two-sided). Twenty millimetres has been identified as the minimum clinically important difference in pain between treatment groups in knee OA studies [12, 13]. Recalculating the power of this study [14] using pain data obtained from participating patients, confirms that the study had 90% power to detect this difference at the 1% level of significance and 97% power to detect this difference at the 5% level.
Statistical analysis
The data were analysed using SPSS.PC version 8.0 statistical software. Analyses were performed on the basis of intention to treat. In the primary analysis, area under the curve (AUC) statistics were calculated for overall pain VAS. For non-completers, AUC was calculated by carrying forward their last recorded pain VAS. This enabled data to be used from all patients who had completed at least 6 weeks of follow-up. Mean AUC pain scores for each treatment group were then compared using two-sided t-tests. Secondary analyses involved AUC analyses for all outcome measures for which there were serial data and calculation of change scores for data with two measurements (range of motion). The patients were then classified as responders or non-responders to treatment on the basis of the Osteoarthritis Research Society International (OARSI) responder criteria for oral NSAIDs in knee OA [15]. These criteria suggest that responders should experience a relative reduction in pain of 45%, with a minimum absolute reduction of 20 mm on a VAS. Patients who experience a more modest reduction in pain (relative reduction 15%, with a minimum absolute reduction of 10 mm) can also be classified as responders if they additionally report an improvement in function (relative change 30%, minimum absolute change 15 points on the WOMAC) or in patient global assessment (relative change 35%, minimum absolute change 10 points). Patient global assessment (of well-being) was not recorded in this trial, so the criteria for large and moderate reductions in pain and function were used.
Assignment
Simple randomization based on random numbers tables was used to assign patients to treatment groups. The patients were assigned randomization numbers sequentially on recruitment to the study and the randomization codes were held by the company who had manufactured the glucosamine and the dummy placebo (Health Perception UK).
Masking
The trial medication for each randomization number was packaged and labelled by the manufacturer (Health Perception UK) and stored in the pharmacy department in the hospital who were responsible for dispensing the medication at each follow-up visit. The packaging and appearance of glucosamine and placebo were identical. Allocation was pre-assigned on the basis of randomization numbers and was concealed from the patients, the investigator and the research nurse who recruited and assessed participating patients, and the pharmacist who dispensed the trial medication. Allocation was revealed when all patients had completed the full follow-up period.
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Results |
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Analysis
The sample had a mean age of 62 yr (S.D. 9.11, range 4294 yr) and a median disease duration of 5 yr (range 148 yr). Sixty-eight per cent (n=54) were female and half the sample identified the right knee as their worst/affected side. The participants reflected a spectrum of symptom and disease severity: median global pain score 52 mm (range 696), median stiffness 57 mm (range 098), median WOMAC function score 36 (range 259), 9% (n=7) Kellgren and Lawrence grade 1, 31% (n=23) grade 2, 37% (n=28) grade 3 and 23% (n=17) grade 4. At baseline, 22.5% were taking analgesics, 46% NSAIDs, 27.5% cod liver oil and 22.5% other complementary therapies.
Baseline comparisons between the treatment groups on demographic variables and all outcome variables confirmed that the randomization had been effective; there were no significant differences between treatment groups on any of the outcome, disease, treatment or demographic variables.
Efficacy data
There were no statistically significant differences in the primary outcome between groups at any time point during the study (Fig. 2).
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OARSI response criteria [15] for relative and absolute reductions in pain and disability were used to classify the patients. The patients could be classified as responders to treatment in two ways:
if their percentage reduction in global pain VAS (baseline to 24 weeks) was greater than 45% and was a minimum absolute reduction of 20 mm);
if their percentage reduction in global pain VAS was less than 45% but greater than 15% (and was a minimum absolute reduction of 10 mm) and their percentage reduction in WOMAC function score was greater than 30% (and was a minimum absolute reduction of 10 points).
Treatment response is summarized in Table 3. There were no statistically significant differences in response between placebo and glucosamine (
2 statistic 0.006, P=0.94).
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Adherence and adverse events
Adherence to prescribed medication is estimated at between 40 and 70% [16, 17]. Adherence to glucosamine and placebo in this trial (assessed by tablet counts) exceeded 80% (glucosamine 84.03%, S.D. 11.76; placebo 83.38%, S.D. 14.51).
No serious adverse effects of treatment were reported during the trial and there were no differences between the treatment groups in the numbers or severity of adverse events reported. There were no significant differences between blood or urine results between groups and no adverse effects of treatment were identified when these results were analysed on an individual patient basis. Table 4 lists all reported side-effects.
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Discussion |
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First, the trial by Reginster et al. [6] was performed on patients with milder symptomatic and less severe structural OA than the patients in our trial. Seventy per cent of the patients in the trial by Reginster et al. had Kellgren and Lawrence grade 2 OA compared with 29% of the patients in our trial and whilst 21% of the patients in our study were Kellgren and Lawrence grade 4, none of the patients in the trial by Reginster et al. was greater than grade 3. Similarly, whilst the patients in our trial had mean WOMAC pain, function and stiffness scores that were around or over the midpoint on the scale, the mean scores for the patients in the trial by Reginster et al. were around or below the 40% mark. In addition, the patients in our trial were more likely to have received previous pharmacological treatment for their OA than the patients in the trial by Reginster et al. and a greater proportion of these were taking NSAIDs (60%) or a combination of NSAIDs and analgesics (22%) than the patients in the trial by Reginster et al. (24% NSAIDs, 8% NSAIDs and analgesics). Our trial was pragmatic and designed to reflect the range of severity of OA symptoms among the sort of UK patients who might be buying and taking glucosamine. The discrepancy between our results and those of the trial by Reginster et al. might suggest that glucosamine has an analgesic effect in mild to moderate OA but not at the more severe end of the spectrum. This hypothesis should be tested in studies adequately powered to perform subgroup analyses for pain and OA severity.
Second, the improvement in pain reported in the glucosamine group in the trial by Reginster et al. was of borderline statistical significance (P=0.047) and small (around 30 mm on a scale of 0500 mm). There was no indication whether such a change was detectable by the patients, or whether they considered it important or adequate.
Although there were differences in inter-participant variance in pain scores in our population of OA patients compared with the published data on which the sample size calculation was based, our trial still had 90% power to detect a difference in treatment effect between the groups at the 1% significance level and 97% power to detect a difference at the 5% significance level, suggesting the trial would have had sufficient power to detect a statistically significant treatment effect between the groups.
Glucosamine appears to be a safe compound when used in patients with OA and there were no adverse effects in the treatment group as judged by both symptoms and blood and urine testing. This compares favourably with the adverse effect profiles of other analgesic treatments for OA such as NSAIDs. Adherence to glucosamine treatment was high and probably reflects the lack of side-effects and a favourable perception of glucosamine as a safe complementary supplement.
In this study we observed a strong analgesic placebo response with a total of 33% patients classified as responders according to OARSI responder criteria. This may be an indication of selection bias in this trial (patients with an affinity for complementary therapies may have been more likely to agree to participate) and has implications for the design of all trials of complementary therapies. The degree of response in some of these patients was impressive and we undertook a qualitative retrospective study on a sample of study patients prior to unblinding, the results of which are reported elsewhere [18].
Interest in complementary therapies in many areas of medicine is growing and patients with chronic diseases, concerned about the possible adverse effects of many orthodox treatments, frequently seek alternatives that are seen as natural and therefore harmless [19]. Clinicians have a responsibility to offer rational, evidence-based advice about complementary therapies, but in many cases this is restricted by the lack of scientifically rigorous evidence. This study has provided some evidence of the safety and relative analgesic effectiveness of glucosamine and, in the process, has highlighted the need for further research to give a definitive answer as to the analgesic role of glucosamine in OA.
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Acknowledgments |
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Rodney Hughes conceived the original idea for the study and wrote the protocol. Angela Huggett and Gillian Glover were the research nurses who recruited the patients, performed the assessments and entered all the outcome data on to the computer. Alison Carr carried out the data analysis. The paper was written by Rodney Hughes and Alison Carr. Rodney Hughes will act as guarantor for the paper.
The research nurses for this trial were funded by an educational grant from Health Perception UK. All trial medication, including dummy placebo, was provided by Health Perception UK. Health Perception UK did not have access to the raw data from the trial and were not involved in any of the data analysis.
Health Perception UK is a manufacturer of glucosamine sulphate.
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Notes |
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References |
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