A confidence interval is a measure of the uncertainty around the main finding of a statistical analysis.

The estimate of an outcome measure is usually presented as a point estimate and a 95% confidence interval.

The 95% confidence interval indicates the range within which the true value of the outcome measure lies — wider intervals indicate lower precision; narrow intervals indicate greater precision.

Effect size is the mean change in an outcome measure divided by the standard deviation of the change.

A positive effect size means that the intervention is more effective than the comparison.

A negative effect size means that the intervention is less effective than the comparison.

Interpretation of effect size is difficult because it is not clear what effect size is clinically meaningful — effect size is a dimensionless ratio. Effect size is used because it allows different outcome measures from different studies to be pooled for meta-analysis.

The Health Assessment Questionnaire (HAQ) was developed as a comprehensive measure of outcome in people with a wide variety of rheumatic diseases, including rheumatoid arthritis, osteoarthritis, juvenile rheumatoid arthritis, lupus, scleroderma, ankylosing spondylitis, fibromyalgia, and psoriatic arthritis. It has also been used in HIV/AIDS and in studies of normal ageing. It should be considered a generic instrument rather than a disease-specific one. Its focus is on self-reported patient-oriented outcome measures, rather than process measures [Fries, 2008].

The odds ratio (OR) is the ratio between the odds of the treated group and the odds of the control group.

OR is a common measure of the size of an effect and may be reported in case-control studies, cohort studies, or clinical trials. It can also be used in retrospective studies and cross-sectional studies, where the goal is to look at associations rather than differences.

A randomized controlled trial (RCT) is a study in which one or more interventions are compared to a control intervention (or no intervention), and participants are randomly allocated to a treatment or control intervention group.

In most trials one intervention is assigned to each individual but sometimes assignment is to defined groups of individuals (for example, in a household) or interventions are assigned within individuals (for example, to different parts of the body or to a particular sequence of study treatments).

The WOMAC (Western Ontario and McMaster Universities osteoarthritis index) is a self-administered questionnaire of disease severity specifically for people with osteoarthritis of the hip or knee [Bellamy, 2001]. It produces an aggregate total score, and scores for three sub-scales: pain, stiffness, and physical functioning/disability. For every question people rate their pain, stiffness, or function as none (score 0), mild (1), moderate (2), severe (3), or extreme (4). Thus, a higher score for each subscale corresponds to a worse condition.

The pain subscale includes five questions on the degree of pain experienced with certain positions and activities (for example, sitting or lying), with the subscore varying from 0 to 20.

The function subscale includes 17 questions on the degree of difficulty experienced while completing activities (for example, descending stairs), with the subscore varying from 0 to 68.

The stiffness subscale includes two questions on severity of stiffness (that is, after first awakening, and later in the day), with the subscore varying from 0 to 8.

WOMAC does not define what would be considered to be a clinically meaningful change. Reductions of 20%, 50% and 70% from baseline WOMAC scores have been suggested and assessed as appropriate goals for treatment [Bellamy et al, 2005].

The weighted mean difference is used in meta-analysis to combine results from a number of different studies, while giving more weight to studies that give us more information.

A number of methods are used to calculate the weighted mean difference. The simplest method uses the number of participants. More complex methods also take into account the number of events, for example by using the variance to give more weight to more precise results.

Evidence from more than 50 observational and qualitative studies on the experience and perceptions of people with osteoarthritis was summarized by the National Institute for Health and Clinical Excellence (NICE). Unsurprisingly, people with osteoarthritis most wanted improvements in pain management and mobility/functional ability, and help with maintaining an independent life in the community. Many people viewed their osteoarthritis symptoms as an inevitable part of getting old, or felt that they were expected to accept their disabilities as inevitable. Depression and anxiety were major problems. Social networks were important in coping with the consequences of osteoarthritis. Treatment decisions were often based on the ability of the person and their partner to cope as a couple. Many people had little, or inaccurate, knowledge of osteoarthritis, and they wanted more information about the condition, self help, and available treatment options. Many people had experienced difficulties in communicating with doctors and some were extremely dissatisfied with the service they had received.

Perceptions of body function and structure (symptoms)

NICE found 10 observational and qualitative studies [National Collaborating Centre for Chronic Conditions, 2008].

Pain, function, and negative feelings were important factors affecting the lives of people with osteoarthritis. People found their pain distressing, and that their osteoarthritis caused limitations and had a major impact on their daily life. The areas that caused major problems were pain, stiffness, fatigue, disability, depression, anxiety, and sleep disturbance.

Perceptions of activities and participation

NICE found nine observational and qualitative studies [National Collaborating Centre for Chronic Conditions, 2008].

Poor performance of tasks was associated with female gender, raised body mass index (BMI), pain, and pessimism. It was embarrassing to be unable to do things their peers could do, and distressing to be unable to participate in valued activities such as travel, leisure activities, social activities, close relationships, community mobility, employment, and heavy housework.

Personal care activities were rarely mentioned.

People with hip osteoarthritis had the worst work-ability scores.

White-collar workers had significantly higher work ability than blue-collar workers, regardless of age.

Perceptions of psychosocial and personal factors: feeling old

NICE found two observational and qualitative studies [National Collaborating Centre for Chronic Conditions, 2008].

Many people viewed their osteoarthritis symptoms as an inevitable part of getting old, and felt that society expected them to accept their disabilities as inevitable.

Perceptions of psychosocial and personal factors: depression, anxiety, life satisfaction

NICE found 11 observational and qualitative studies [National Collaborating Centre for Chronic Conditions, 2008].

Older people with advanced osteoarthritis felt that the disease threatened their self-identity, they were overwhelmed by health and activity changes, and they felt powerless to change their situation.

Depression and anxiety were major problems.

Factors that were associated with depression, anxiety, and less life satisfaction included:

Physical outcome measures.

Pain.

Lack of social support.

Pessimism.

Measures of depression, anxiety, and life satisfaction were worse in:

People with osteoarthritis of the hip (compared with osteoarthritis of other joints).

White collar workers (compared with blue collar workers).

Men (compared with women).

Perceptions of psychosocial and personal factors: relationships

NICE found three observational and qualitative studies [National Collaborating Centre for Chronic Conditions, 2008].

Informal social networks (family, friends, and neighbours) helped with tasks, gave emotional support, helped keep people socially involved, and could support the idea that surgery is avoidable.

Decisions on treatment were made on the basis of the coping ability of the couple, not just the coping ability of the partner disabled by osteoarthritis.

Perceptions of psychosocial and personal factors: knowledge of arthritis and its management

NICE found six observational and qualitative studies [National Collaborating Centre for Chronic Conditions, 2008].

Most people thought their osteoarthritis was a normal and inevitable result of hardship or hard work. However, younger respondents did not perceive their symptoms as being normal, and were more determined to get treatment.

Many people had little knowledge of:

The causes and outcome of osteoarthritis.

Suitable forms of exercise.

The benefits of lifestyle changes.

Management of an acute episode.

The aims of treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) — many thought that NSAIDs would slow progression of their osteoarthritis.

The adverse effects of treatment with NSAIDs and intra-articular corticosteroid injections.

Aids and devices.

Perceptions of psychosocial and personal factors: expectations of treatment

NICE found three observational and qualitative studies [National Collaborating Centre for Chronic Conditions, 2008].

People most wanted improvements in pain management and mobility/functional ability, and help with maintaining an independent life in the community.

Perceptions of psychosocial and personal factors: use of self-management methods

NICE found five observational and qualitative studies [National Collaborating Centre for Chronic Conditions, 2008].

Use of self-management methods was associated with more education, more social support, more symptoms, and more serious symptoms, but not with age or gender.

People were embarrassed by their disabilities and felt stigmatized when using walking aids or wheelchairs.

Many people used alternative therapies such as ginger, cod-liver oil, acupuncture, magnets, and others.

People wanted more information about the condition, and about self help and available treatment options.

Perceptions of psychosocial and personal factors: treatment/healthcare

NICE found seven observational and qualitative studies [National Collaborating Centre for Chronic Conditions, 2008].

Perceptions of provision of treatment

Older people and women were more likely to rate their treatment as more helpful. People with higher occupational status were more likely to feel more negatively about their treatment.

The longer the delay between the onset of symptoms and the diagnosis of osteoarthritis, the more difficult it was for people to deal with their symptoms.

Younger people attributed delays in their diagnosis to healthcare professionals considering them too young to have osteoarthritis.

The unpredictable nature and invisibility to others of symptoms were barriers to receiving support (noted mainly by younger people with osteoarthritis).

People felt that there was a real lack of information and support given to them (by their GP and other primary care team members) about their condition, especially in the areas of managing pain and coping with daily activities. Obtaining information and more visits to the doctor were associated with reporting more symptoms and with believing treatment to be more helpful.

Many people had experienced difficulties communicating with doctors and some were extremely dissatisfied with the service they had received. Common problems were:

An inadequate supply of medications to last until their next GP appointment.

Gastrointestinal (GI) problems.

Barriers to attending the clinic (for example, finances, transportation).

Barriers when rapid intervention was required.

Several people noted that their family physician had never discussed surgery with them and they therefore assumed that surgery was not possible. Where surgery had been mentioned by healthcare professionals it was often described as a last resort.

Perceptions of surgery

Employed younger respondents had all paid for private referrals to specialists and had all undergone, or were being considered for, total joint replacement surgery.

Perceptions of drugs

Drugs were seen as helpful by many people.

However, many people were unwilling to use medication because they thought medication would mask (rather than cure) symptoms, and would have adverse effects.

Perceptions of aids to daily living:

Canes were perceived as useful but some people felt too embarrassed to use them.

Perceptions of physiotherapy and exercise:

Physiotherapy and regular exercise were seen as beneficial treatments.

The evidence from two systematic reviews/meta-analyses and eight other studies is that the benefits of education and self-management for people with osteoarthritis is limited. However, methodological problems commonly present in the studies may have influenced the results.

Two systematic reviews and meta-analyses, six RCTs, one implementation study, and one observational study were included in the review by the National Institute for Health and Clinical Excellence (NICE) of studies on education and self-management methods for people with osteoarthritis [National Collaborating Centre for Chronic Conditions, 2008]. Studies varied in the site of osteoarthritis (mostly hip or knee), in the education/self-management programme (with respect to content, length, and delivery method), and in the outcome measures. Outcomes included pain, stiffness, function/disability, quality of life, self-efficacy (a person's perception of their ability to manage their osteoarthritis), use of health services, use of analgesia, knowledge of osteoarthritis, and use of self-management methods. Most outcomes were reported by NICE as effect sizes.

Some studies found a small improvement, while other studies found no statistically significant effect.

NICE commented that methodological limitations in the studies included:

Range and diversity of outcomes measured.

Disparities in severity and site of osteoarthritis.

Few studies explored self-efficacy and wider psychological and social factors.

Outcomes were likely to have been influenced by the negative expectations of people with osteoarthritis (and to some extent by those of healthcare professionals), and by poor access to support and advice.

The National Institute for Health and Clinical Excellence (NICE) found no relevant studies on the effect of rest, relaxation, or pacing of activity on osteoarthritis [National Collaborating Centre for Chronic Conditions, 2008].

There is no evidence on the effect of hot packs, and little weak evidence on the effect of cold thermotherapy on osteoarthritis.

The National Institute for Health and Clinical Excellence (NICE) found three small RCTs of the effect of cold packs on osteoarthritis, one of which assessed pain relief [National Collaborating Centre for Chronic Conditions, 2008].

Pain

One RCT found no significant difference between cold thermotherapy and control.

Function

Three RCTs had inconsistent/mixed results.

There is strong evidence from a systematic review of a large number of RCTs, and subsequent RCTs, that for osteoarthritis of the knee, exercise reduces pain, disability, and medication intake, and improves physical functioning, stair climbing, walking distance, muscle strength, balance, self-efficacy, and mental health. A few studies suggest that exercise may be beneficial for people with osteoarthritis of the hand or hip (although the mechanisms may be different). There is no good evidence that one type of exercise is superior to any other type. Exercise delivered in a class and supplemented by exercise at home may be superior to home exercise alone, and appears to be cost effective. Two RCTs suggest that exercise in water may have short-term benefits. Adverse events were inconsistently studied, but the National Institute for Health and Clinical Excellence (NICE) consider the risk to be low if the suitability of the exercise for the individual is appropriately assessed by a trained healthcare professional.

Exercise may be targeted at individual joints, or at general fitness. It may be taken at home, or in a supervised class in which the instructor may lead a group or an individual. Exercise may be taken on land or in water. Exercise interventions include aerobic walking, quadriceps exercise, strengthening and home exercise, aerobic exercise with weight training, and diet with aerobic and resisted exercise.

NICE conducted a systematic review of the effects of exercise on osteoarthritis [National Collaborating Centre for Chronic Conditions, 2008].

The review addressed two types of question:

Is exercise more effective than no exercise or other treatments?

Are the risks and benefits of one type of exercise preferable to those of other types of exercise?

Different studies used a number of different interventions for people with differing types and severity of osteoarthritis and assessed the outcomes with a number of different measures over a range of follow-up times.

Land-based exercise

Evidence on the first question was provided by 29 RCTs. Evidence on the second question was provided by nine RCTs.

Osteoarthritis of the knee

Exercise reduced pain, disability, and medication intake, and improved physical functioning, stair climbing, walking distance, muscle strength, balance, self-efficacy, mental health, and physical functioning. The majority of these beneficial outcomes were seen at 18 months.

Osteoarthritis of the hand or hip

A few studies provided inconclusive and/or indirect evidence of effectiveness.

Economic analysis

NICE found four economic studies that met their review criteria.

One well-conducted study provided evidence relevant to the UK. It found that supplementing a home-based exercise programme with a class-based programme is cost saving or cost effective. If travel costs were included, it is probable that the class-based supplement would still be cost effective.

Adverse effects

No serious adverse effects of exercise were identified by NICE.

Exercise in water (hydrotherapy/aquatic exercise):

NICE found six RCTs that met their criteria for inclusion in the review.

There is mixed, but mostly positive, evidence to suggest that exercise in water may be beneficial in the short term with respect to pain, stiffness, function/disability, muscle strength, and quality of life.

Methodological weaknesses were commonly present in the studies, and included lack of blinding, flaws in randomization, small sample sizes, absence of power calculations, and no information on intention-to-treat analyses.

Manual therapy

Manual therapies include joint manipulation, mobilization, and stretching, with or without exercise.

Most studies evaluated manual therapy for osteoarthritis in combination with other treatment approaches, for example exercise. This reflects current practice in physiotherapy, where manual therapy would not be used as a sole treatment for osteoarthritis but as part of a package of care.

Osteoarthritis of the hip

One RCT and one observational study provide evidence, consistent for a number of outcome measures, that manual therapy is more effective than exercise.

Osteoarthritis of the knee

Seven studies provide mixed but mainly favourable evidence, for a number of outcome measures, that manual therapy is more effective than exercise.

Adverse effects

No serious adverse effects of manual therapy were identified by NICE.

Methodological weaknesses were commonly present in the studies, and included lack of blinding, flaws in randomization, small sample sizes, absence of power calculations, and no information on intention-to-treat analyses.

Evidence from five RCTs of weight loss in people with osteoarthritis of the knee suggests that function can be improved, provided the weight loss is sufficient. Results on the effect on pain were inconsistent, and difficult to distinguish from possible effects of exercise, as, in the most informative RCT, exercise was part of a complex intervention to lose weight. There is no evidence that weight loss (with or without exercise) can slow the progression of osteoarthritis. There is no evidence on the effects of weight loss on osteoarthritis of the hip, hand, or other joints.

The National Institute for Health and Clinical Excellence (NICE) conducted a systematic review of the effects of weight loss on osteoarthritis [National Collaborating Centre for Chronic Conditions, 2008]. Evidence was summarized from one systematic review, and meta-analysis of four RCTs and one additional RCT. All five RCTs studied people with osteoarthritis of the knee. NICE found no trials assessing the effect of weight loss on osteoarthritis of other joints.

Pain

The meta-analysis found that weight loss had no significant effect on pain.

Function/disability

The meta-analysis found significant effects on self-reported disability but not on global disability.

Quality of life

One RCT (n = 316) compared the effects of four interventions on the quality of life reported by people with osteoarthritis of the knee: dietary weight loss alone, exercise alone, dietary weight loss plus exercise, or healthy lifestyle control.

Compared with the healthy lifestyle control group, the dietary weight loss group were significantly more satisfied with their functioning. However, on nine other measures of quality of life, the differences were not significant.

The other between-group comparisons had similar mixed results.

Ultrasound: there is evidence from three RCTs that ultrasound has no benefit in the treatment of knee and hip osteoarthritis.

Laser therapy: there is evidence from nine RCTs that laser therapy has no benefit in the treatment of osteoarthritis (multiple joints).

Transcutaneous electrical nerve stimulation (TENS, AL-TENS, interferential therapy): there is mixed, but mostly positive evidence from 10 RCTs that TENS may relieve the pain and stiffness of knee osteoarthritis, especially in the short term. There is no evidence that efficacy tails off over time, nor that periodic use for exacerbations is helpful.

Pulsed electromagnetic field (PEMF): there is limited evidence from systematic reviews of RCTs that PEMF may relieve pain and improve function in people with knee osteoarthritis. There is no evidence on the effects of PEMF on osteoarthritis in other joints.

The National Institute for Health and Clinical Excellence (NICE) conducted a systematic review of the effects of electrotherapy: ultrasound; laser; TENS, TNS, AL-TENS, and interferential therapy; and pulsed shortwave diathermy (PEMF) on osteoarthritis [National Collaborating Centre for Chronic Conditions, 2008]. Five systematic reviews and meta-analyses were found on electrotherapy (laser, electromagnetic fields, ultrasound, and TENS) and six additional RCTs on laser, electromagnetic fields, and TENS.

Ultrasound

One systematic review/meta-analysis of three RCTs was found on the use of ultrasound for people with knee or hip osteoarthritis.

Pain, function/disability, and global assessment: no significant benefits.

Laser

One systematic review/meta-analysis of seven RCTs, and two further RCTs were found on the use of laser therapy in people with osteoarthritis.

Pain: one of three comparisons favoured laser therapy, but the clinical importance is unclear.

Stiffness, function, global assessment, quality of life: no significant benefits.

TENS, including AL-TENS and interferential therapy

One systematic review/meta-analysis of seven RCTs, and three further RCTs, were found on the use of TENS in people with osteoarthritis.

Pain, stiffness, function/disability, quality of life: mixed results from different measures of pain, some favouring TENS/AL-TENS, some not significant, and a few favouring the comparator.

PEMF

Two systematic reviews/meta-analyses (reviewing six RCTs, and five RCTs respectively) were found on the use of PEMF in people with knee osteoarthritis.

Pain: significant benefits for three of four measures of pain.

Stiffness: no significant benefits.

Function/disability: significant benefits for three of four measures of function/disability.

Global assessment: significant benefits of physician's global assessment, but not for patient's global assessment.

Quality of life: significant benefits for two of three measures of quality of life.

Evidence from a systematic review/meta-analysis of eight RCTs of acupuncture for osteoarthritis of the knee, and from a further six RCTs, provides weak support for the use of acupuncture (traditional Chinese acupuncture or Western medical; manual, or electro-acupuncture). Results were mixed, with some trials showing effectiveness, others failing to reach statistical significance, and a few favouring the comparator intervention. Few studies lasted longer than 12 weeks, so the evidence on longer-term outcomes is limited. The National Institute for Health and Clinical Excellence (NICE) conducted a cost-consequence study and concluded that electro-acupuncture was not cost-effective, but the data were insufficient to recommend whether or not acupuncture should be regarded as affordable by the NHS.

Background

Acupuncture in traditional Chinese medicine is a treatment in which fine needles are used to stimulate specific points identified by traditional practitioners. Acupuncture, as practised in Western medicine, places about six needles near the painful area, and possibly elsewhere. The needles are manipulated or stimulated electrically (electro-acupuncture) to produce a particular needle sensation. A course of treatment usually consists of six or more sessions.

Evidence summary

NICE conducted a systematic review of the effects of acupuncture (traditional Chinese acupuncture, Western medical acupuncture, and electro-acupuncture) on osteoarthritis [National Collaborating Centre for Chronic Conditions, 2008].

One systematic review/meta-analysis and six additional relevant RCTs were found.

The systematic review/meta-analysis included eight RCTs (n = 2362) of osteoarthritis of the knee.

RCTs differed in the joints treated, types of acupuncture, comparisons made (with sham acupuncture or an active treatment), study size, and duration of follow up.

Pain

Acupuncture. The meta-analysis found statistically significant benefits in three of six comparisons with no additional treatment or with sham treatments. However, the changes were small and may not be clinically important.

Hip: one RCT found no significant benefit.

Thumb: one small RCT (n = 13) reported mixed results for different measures of pain.

Knee or hip: one RCT (n = 712) found a statistically and clinically significant benefit.

Mixed (knee, hip, finger, spine): one RCT (n = 40) found no significant benefit.

Stiffness

Acupuncture.

Knee or hip: one RCT (n = 712) found a statistically and clinically significant benefit.

Mixed (knee, hip, finger, spine): one RCT (n = 40) found no significant benefit.

Function/disability

Acupuncture.

Hip: one RCT (n = 67) found no significant benefit.

Thumb: one small RCT (n = 13) found no significant benefit.

Knee: one meta-analysis (four RCTs, n = 1245) found small statistically significant improvements in two of six analyses.

Knee or hip: one RCT (n = 712) found a statistically and clinically significant benefit.

Mixed (knee, hip, finger, spine): one RCT (n = 40) found no significant benefit.

Long term (mixed): three RCTs (n = 1178); WMD 2.01 (95% CI 0.36 to 3.66, p < 0.05) — clinical importance not stated.

Global assessment

Acupuncture.

Hip: one RCT (n = 67) found no significant benefit at 6 weeks post intervention, but a significant improvement of 9% in reported satisfaction.

Quality of life

Acupuncture.

Hip: one RCT (n = 67) found no significant benefit.

Knee or hip: one RCT (n = 712) found statistically significant benefit in measures of physical and mental quality of life.

Other outcomes

Acupuncture.

Knee or hip: one RCT (n = 712) found a statistically and clinically significant difference in the proportion of people regarded as responders on the WOMAC score.

Thumb: one small RCT (n = 13) found no significant benefit on a verbal rating of improvement.

Adverse events

Acupuncture: no serious adverse events were reported.

Electro-acupuncture: no serious adverse events were reported.

Health economic studies

The published evidence on health economics is limited and not easily applicable to the UK. NICE therefore conducted a cost-consequence study.

Acupuncture

The incremental cost-effectiveness ratio for acupuncture may be higher than the threshold typically used by the NHS to assess affordability. However, limitations in the data mean that there is considerable uncertainty in the estimate of cost-effectiveness.

Electro-acupuncture

Electro-acupuncture was considered to be definitely above the threshold of affordability.

Limitations of the studies

Included studies were all of high methodological quality.

Few studies lasted more than 12 weeks, so the evidence on long-term effects is limited, but suggests that function may be improved.

NICE selected one study of electro-acupuncture for review, but did not include other trials that used electro-acupuncture, for example [Berman et al, 2004; Vas et al, 2004].

If these trials had been included in the NICE review, the evidence for the effectiveness of electro-acupuncture would appear stronger.

These trials, however, were included in the systematic review summarized by NICE and used to assess the evidence for acupuncture.

Although the analyses used clinically relevant outcome measures (e.g. pain, function), it is difficult to assess how clinically important the benefits are.

There are few well designed trials on footwear, bracing, and walking aids. There is limited and weak evidence to support the use of footwear, bracing, and walking aids.

The National Institute for Health and Clinical Excellence (NICE) conducted a systematic review of the efficacy and safety of footwear, bracing, and walking aids [National Collaborating Centre for Chronic Conditions, 2008].

One Cochrane systematic review/meta-analysis and 13 additional relevant RCTs were found.

The systematic review/meta-analysis included four RCTs (n = 444) which studied insoles and limb braces in people with osteoarthritis of the knee.

The RCTs differed in the interventions, comparisons, study size, duration of follow up, and methodological quality (susceptibility to biased results).

Eleven of the additional RCTs studied osteoarthritis of the knee, and two studied osteoarthritis of the thumb.

Knee osteoarthritis

Knee brace

Knee pain on walking/climbing stairs: one RCT (n = 119) found a knee brace was more effective than a neoprene sleeve, and more effective than medical treatment.

Knee pain severity: one RCT (n = 118) found a knee brace provided no additional benefit over medical treatment.

Function/disability: one RCT (n = 119) found a knee brace to be more effective than neoprene sleeve, and more effective than medical treatment on the WOMAC score, but not on other measures.

Quality of life: one RCT (n = 118) found a knee brace provided no additional benefit over medical treatment.

Serious adverse events: none reported.

Neoprene sleeve

Knee pain on walking/climbing stairs: one RCT (n = 119) found a neoprene sleeve was more effective than medical treatment.

Function/disability: one RCT (n = 119) found a neoprene sleeve was more effective on WOMAC score than medical treatment.

Serious adverse events: none reported.

Insoles

Knee pain severity: one RCT (n = 147) found insoles provided no significant benefit.

Stiffness: two RCTs (n = 147 and n = 156) found insoles provided no significant benefit.

Function/disability: in three RCTs (n = 147, n = 90, and n = 156), one of six comparisons favoured insoles over no or neutral insoles.

Global assessment: two RCTs (n = 147 and n = 146) found insoles provided no significant benefit.

Use of analgesics: two RCTs (n = 147 and n = 146) found insoles provided a significant benefit in one of four comparisons.

Serious adverse events: none reported.

Patella taping

Knee pain severity: two RCTs (n = 14 and n = 87) found medial/therapeutic taping significantly more effective than lateral/control taping on most measures of pain.

Function/disability: one RCT (n = 87) found medial/therapeutic taping significantly more effective than lateral/control taping on four out five measures of function/disability.

Personal preference: one RCT (n = 14) found medial taping was preferred over neutral taping; there was no preference over lateral taping.

Use of analgesics: one RCT (n = 87) found no significant benefit of taping.

Quality of life: one RCT (n = 87) found therapeutic taping to be significantly more effective than control taping in seven out of eight measures of quality of life.

Serious adverse events: none reported.

Shoes

Knee pain severity: one RCT (n = 125) found no significant difference between the 'Masai barefoot technology^'® shoe and a high-end walking shoe.

Stiffness: one RCT (n = 125) found no significant difference between the 'Masai barefoot technology'^® shoe and a high-end walking shoe.

Serious adverse events: none reported.

Walking stick

Walking speed, steps/minute: one RCT (n = 14) found walking to be significantly improved with both ipsilateral and contralateral cane.

Stride length: one RCT (n = 14) found no significant difference.

Serious adverse events: none reported.

There are few well designed trials on assistive devices used by people with osteoarthritis. Surveys show that assistive devices and aids are well accepted by many people, but most people consider them awkward to use and expensive to buy, and many felt that they made them feel more dependent.

The National Institute for Health and Clinical Excellence (NICE) conducted a systematic review of the efficacy and safety of aids and devices on osteoarthritis [National Collaborating Centre for Chronic Conditions, 2008].

One RCT and four observational studies were found.

The studies differed with respect to study design, site of osteoarthritis, interventions, study size, and outcomes measured.

Hand osteoarthritis

Pain: one RCT (n = 40) found a significant benefit from the addition of exercise to assistive devices.

Grip strength: one RCT (n = 40) found a significant benefit from the addition of exercise to assistive devices.

Function/disability (change in HAQ score): one RCT (n = 40) found no significant difference.

Hip or knee osteoarthritis

Use of assistive devices: two observational studies (n = 27 and n = 88) found that assistive devices were used by 59% and 56% of respondents.

Personal satisfaction: two observational studies (n = 27) found that assistive devices were rated by 30% of respondents as one of the three most effective treatments.

Site of osteoarthritis not specified

Use of assistive devices: one observational study (n = 248) found that assistive devices were used by 67% of respondents.

Positive attitude towards assistive devices: one observational study (n = 248) found that on three different measures, more than 90% of respondents had a positive attitude towards assistive devices.

Negative attitude towards assistive devices: one observational study (n = 248) found that assistive devices were considered awkward by 79% of respondents, too expensive to buy themselves by 59% of respondents, and made them more dependent by 48% of respondents.

Eight RCTs provide weak and inconsistent evidence that arthroscopic lavage and debridement, or tidal irrigation, are beneficial for osteoarthritis of the knee.

Background

Arthroscopic lavage and debridement involves:

Arthroscopy — insertion of a fibreoptic instrument into the knee and inspection for disease, requiring a general anaesthetic.

Lavage — irrigation of the joint with a large volume of fluid, which may remove microscopic and macroscopic debris resulting from cartilage breakdown, as well as removing the pro-inflammatory effects of this material.

Debridement — surgical removal of obviously frayed cartilage or meniscal surfaces.

Tidal irrigation involves irrigating the joint through a needle inserted into the knee joint under local anaesthesia; a large volume of fluid is run into the knee and then allowed to drain out. The rationale is the same as for arthroscopic lavage.

Evidence summary

The National Institute for Health and Clinical Excellence (NICE) conducted a systematic review of the efficacy and safety of arthroscopic lavage, debridement, and tidal irrigation for osteoarthritis of the knee [National Collaborating Centre for Chronic Conditions, 2008].

Eight relevant RCTs were found assessing invasive treatments of osteoarthritis of the knee. The studies differed with respect to comparisons, numbers of participants, and duration of follow up.

Lavage for knee osteoarthritis

Pain: four RCTs (n = 180, n = 34, n = 20, n = 98). One of the four RCTs found significant benefits for lavage. Each study used several different measures of pain, and results were consistent within studies.

Stiffness: one RCT (n = 20). Results were inconsistent: one measure of stiffness (gelling) favoured the use of lavage, while the other measure (duration of morning stiffness) did not.

Function/disability: four RCTs (n = 180, n = 34, n = 20, n = 98). No significant benefits for lavage. Studies used several different measures of function/disability, and results were consistent within studies.

Global assessment: two RCTs (n = 34, n = 98). The larger study found no benefits for lavage, and results were inconsistent in the smaller study.

Quality of life: one RCT (n = 34). No benefits for lavage were found on three different measures of quality of life.

Tidal irrigation for knee osteoarthritis

Pain: three RCTs (n = 180, n = 77, n = 90). The two smaller RCTs found significant benefits for irrigation. Each study used several different measures of pain, and results were consistent within studies.

Stiffness: three RCTs (n = 180, n = 77, n = 90). The smallest RCT found significant benefits for irrigation. One study used two different measures of stiffness, and its results were consistent.

Function/disability: three RCTs (n = 180, n = 77, n = 90). No significant benefits for irrigation. Studies used several different measures of function/disability, and results were consistent within studies.

Global assessment: two RCTs (n = 180, n = 77). The smaller study found benefits for irrigation, while the larger study found no difference between irrigation and control treatment.

Quality of life: one RCT (n = 180). No benefits for irrigation were found.

Use of rescue medication/analgesia: one RCT (n = 180). No benefits for irrigation were found.

Osteoarthritis of the knee: three small RCTs found that intra-articular corticosteroid injections were consistently more effective than placebo for a range of pain and function outcome measures.

Osteoarthritis of the hip: two small RCTs had mixed results that do not provide good evidence to support intra-articular corticosteroid injections of the hip.

Osteoarthritis of the thumb: one small RCT found no significant benefit for intra-articular corticosteroid injections.

Expert opinion is that there is a very small risk of serious adverse effects such as infection.

The National Institute for Health and Clinical Excellence (NICE) reviewed studies on the efficacy and safety of intra-articular injection of corticosteroids in adults with osteoarthritis and found one meta-analysis and three further RCTs [National Collaborating Centre for Chronic Conditions, 2008].

Knee osteoarthritis: intra-articular corticosteroids compared with placebo

A meta-analysis of data from three RCTs with 156 participants found that intra-articular corticosteroid injections were more effective than placebo in terms of:

Average number of knees improved at 2 weeks post injection (one RCT, n = 71): RR 1.81 (95% CI 1.09 to 3.00, p = 0.02).

At least 30% decrease in baseline pain at 1 week post injection (one RCT, n = 53): RR 2.56 (95% CI 1.26 to 5.18, p = 0.009).

At least 15% decrease in baseline pain at 3 weeks post injection (one RCT, n = 118): RR 3.11 (95% CI 1.61 to 6.01, p = 0.0006).

Change in pain at 1 week post injection (three RCTs, n = 161): WMD –21.91 (95% CI –29.93 to –13.89, p = 0.00001).

Change in pain at 12 weeks post injection (one RCT, n = 53): WMD –14.20 (95% CI –27.44 to –0.96, p = 0.04).

Change in pain at 1 year post injection (one RCT, n = 66): WMD –13.80 (95% CI –26.79 to –0.81, p = 0.04).

Number of people preferring intra-articular corticosteroids (three RCTs, n = 190): RR 2.22 (95% CI 1.57 to 3.15, p < 0.00001).

Overall improvement (three RCTs, n = 156): RR 1.44 (95% CI 1.13 to 1.82, p = 0.003).

Hip osteoarthritis: intra-articular corticosteroids compared with placebo

An RCT (n = 101 in three arms) found that compared with saline injections, intra-articular corticosteroid injections were:

More effective in terms of pain on walking: effect size (ES) 0.6 (95% CI 0.1 to 1.1, p = 0.021).

No significant difference in terms of patient's global assessment and OARSI (Osteoarthritis Research Society International) measures at 2, 4, and 12 weeks after injection.

An RCT (n = 30) found no significant difference between intra-articular corticosteroid injections and placebo in terms of pain relief at 1, 3, and 12 months after injection.

Thumb osteoarthritis: intra-articular corticosteroids compared with placebo

An RCT (n = 40) found no significant difference between intra-articular corticosteroid injections and placebo in terms of pain relief, joint stiffness, joint tenderness, or patient and physician global assessments at 12, and 24 weeks after injection.

Safety

No serious adverse effects were reported in the included studies.

The experts in the guideline development group agreed that:

The risks associated with intra-articular corticosteroid injection are generally small.

A small percentage of people may experience a transient increase in pain following injection.

Subcutaneous deposition of steroid may lead to local fat atrophy and cosmetic defect.

Care should always be taken when injecting small joints (such as finger joints) to avoid traumatizing local nerves.

There is a very small risk of infection.

The question of steroid-arthropathy (i.e. whether intra-articular steroids may increase cartilage loss) remains controversial; concern is currently based on animal models and retrospective human studies. Caution should be applied if injecting an individual joint on multiple occasions, and other osteoarthritis therapies should be optimized.

In people with osteoarthritis of the knee, there is a large body of poor quality evidence to suggest that intra-articular injection of hyaluronan/hyaluronic acid (HA) derivatives provide short-term symptomatic relief. Several poor quality studies found that intra-articular HA may reduce pain and improve function compared with placebo, with the greatest effect being up to 13 weeks after injection. Compared with intra-articular corticosteroids, data from three small RCTs suggests that HA may be more effective at reducing pain at 5–13 weeks. No significant differences in adverse effects were found between HA derivatives and placebo. Heterogeneity between trials is partially due to the number of different HA derivatives available. The National Institute for Health and Clinical Excellence (NICE) Guideline Development Group decided that HA use is not currently a cost-effective option for the NHS.

NICE investigated the efficacy and safety of intra-articular injection of HA (compared with placebo or corticosteroid injection) with respect to symptoms, function, and quality of life in adults with osteoarthritis.

Two Cochrane reviews were found of people with osteoarthritis of the knee [Bellamy et al, 2006a; Bellamy et al, 2006b]. Four RCTs were found that were published subsequently. One of these RCTs was excluded by NICE due to multiple methodological limitations and the other three RCTs reinforced the findings of the Cochrane reviews, and so are not discussed further.

The first Cochrane review (40 RCTs, n = 5257) assessed the effects of viscosupplementation (intra-articular hyaluronan and hyaluronan derivatives) compared with intra-articular placebo in people with osteoarthritis of the knee [Bellamy et al, 2006b]. Literature searches were performed up to the end of 2005.

Intra-articular HA injection compared with placebo

In people with osteoarthritis of the knee, the evidence suggested that compared with placebo, HA derivatives generally had superior efficacy in a range of outcomes (pain relief, stiffness in knee, function improvement, patient global assessment, and quality of life) at various time points, but especially in the 5- to 13-week post-injection period.

The adverse event profiles were generally found to favour placebo. No major safety issues were identified, but sample sizes were limited.

In people with osteoarthritis of the hip, no significant differences were reported in efficacy and function outcomes between HA and placebo at any time point.

The effect of HA compared with placebo on weight-bearing pain at:

1–4 weeks post injection: significantly improved (22 RCTs: WMD –7.7, 95% CI –11.3 to –4.1, p < 0.0001).

5–13 weeks post injection: significantly improved (17 RCTs: WMD –13.0, 95% CI –17.8 to –8.2, p < 0.00001).

14–26 weeks post injection: significantly improved (nine RCTs: WMD –9.0, 95% CI –14.8 to –3.2, p = 0.002).

At 45–52 weeks post injection: no improvement was found (as indicated by three RCTs).

The effect of HA compared with placebo on Lequesne Index at:

1–4 weeks post injection: significantly improved (four RCTs: WMD –0.8, 95% CI –1.5 to –0.2, p = 0.02).

5–13 weeks post injection: significantly improved (four RCTs: WMD –1.4, 95% CI –2.0 to –0.7, p < 0.0001).

At 14–26 weeks post injection or later: no significant difference was found.

The second Cochrane review (28 RCTs, n = 1973) evaluated the efficacy and safety of intra-articular corticosteroids in people with osteoarthritis of the knee [Bellamy et al, 2006a]. Literature searches were performed up to the beginning of January 2006. Studies differed in the type of HA used, mode of HA production, type of corticosteroid used, treatment regimens, trial design, trial size, and trial duration. The efficacy of HA was often difficult to interpret because of some of these confounders. The Cochrane review pooled all data for symptoms, function and adverse effects but quality of life outcomes were not reported.

Intra-articular HA injection compared with intra-articular corticosteroid

In people with osteoarthritis of the knee, no significant difference in pain levels was found between intra-articular corticosteroids and HA at 1–4 weeks after injection. However, HA was significantly more effective than corticosteroids in reducing pain at 5 and 13 weeks, suggesting that intra-articular HA may have a more prolonged effect:

At 1–4 weeks after injection (three RCTs [n = 85]: WMD –4.90, 95% CI –9.91 to +0.10, p = 0.05).

At 5–13 weeks after injection (three RCTs: WMD –7.73, 95% CI –12.81 to –2.64, p = 0.003).

In people with osteoarthritis of the hip and hand, no significant differences between HA and intra-articular corticosteroids were reported at any time point by the two studies evaluating efficacy and function outcomes.

There were no significant differences in adverse event outcomes between HA and intra-articular corticosteroids.

When economically evaluating the role of HA, the NICE Guideline Development Group found that despite the (generally small) beneficial effect of HA, from a cost-effectiveness perspective the efficacy would have to be three to five times higher than the estimates from the trials before reaching the standard threshold for cost effectiveness for the NHS.

[National Collaborating Centre for Chronic Conditions, 2008]

The evidence supporting the use of opioid analgesia in osteoarthritis is poor, but available trial data show that, compared with placebo, opioid analgesics reduce pain in people with osteoarthritis of the knee. There are a lack of trials comparing the efficacy and safety of opioids with other symptomatic treatments for osteoarthritis, and there are virtually no good studies using opioids in people with peripheral joint osteoarthritis, so the benefits of opioids in different types of osteoarthritis remains unclear. There is little evidence to suggest that increasing the opioid dose improves the effect. There are also few data comparing different opioid formulations or routes of administration. The adverse effects of opioids are a concern, especially in elderly people.

The National Institute for Health and Clinical Excellence (NICE) looked at studies that investigated the efficacy and safety of opioids or opioid–paracetamol compounds compared with other treatment options, with respect to symptoms, function, and quality of life in adults with osteoarthritis. Two systematic reviews were appraised [Cepeda et al, 2006; Bjordal et al, 2007].

A Cochrane review (11 RCTs, n = 1019) compared the efficacy and safety of tramadol or tramadol/paracetamol with placebo or active control in people with osteoarthritis [Cepeda et al, 2006]. Literature searches were performed up to August 2005.

Efficacy of opioid analgesics compared with placebo

A meta-analysis of three RCTs (n = 749), ranging from 14–91 days, compared the effect of tramadol, tramadol–paracetamol in combination, and paracetamol alone in people with osteoarthritis (mainly of the knee).

In terms of pain intensity, the analysis found a mean difference of –8.47 (95% CI –12.1 to –4.9, p < 0.00001), favouring the opiod/opioid–paracetamol combination.

Tramadol was found to significantly reduce pain intensity and total WOMAC score compared with placebo:

Pain intensity (WMD –8.47, 95% CI –12.05 to –4.90)

WOMAC score (WMD –0.34, 95% CI –0.49 to –0.19)

RR 1.37, 95% CI 1.22 to 1.55

Efficacy of opioid analgesics compared with each other

Three RCTs were evaluated that compared tramadol versus dihydrocodeine, dextropropoxyphene, and pentazocine. Tramadol increased the likelihood of a moderate improvement by 38% compared with dextropropoxyphene, and by 150% compared with pentazocine (absolute data and p-value not reported).

Safety of opioid analgesics compared with placebo

The Cochrane review found that tramadol increased the risk of developing major adverse events by 2.6 times (95% CI 2.0 to 3.6) compared with placebo:

Tramadol — 143/710 (20%)

Placebo — 49/626 (8%)

Number needed to harm: 8 (95% CI 7 to 12)

Safety of opioid analgesics compared with each other

The systematic review found that tramadol caused significantly more adverse events than dextropropoxyphene:

Tramadol — 48/135 (36%)

Dextropropoxyphene — 14/129 (11%)

Number needed to harm: 6 (95% CI 4.4 to 12.0)

Tramadol was also found to cause fewer adverse events than pentazocine, but the p-value was not reported:

Tramadol — 9/30 (30%)

Pentazocine — 11/30 (37%)

A second systematic review (63 RCTs, n = 14,060) investigated the short-term pain relieving effects of seven commonly used drugs in people with osteoarthritis of the knee [Bjordal et al, 2007].

Efficacy of opioid analgesics compared with placebo

In people with moderate-to-severe pain, opioids had maximum efficacy at 2–4 weeks compared with placebo:

Six RCTs (n = 1057), mean difference 10.5 (95% CI 7.4 to 13.7).

Safety of opioid analgesic compared with placebo

Withdrawal rate — opioids were associated with high withdrawal rates (20–50%) compared with placebo (about 10%).

[National Collaborating Centre for Chronic Conditions, 2008]

A large amount of clinical trial evidence supports the efficacy of both standard nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 selective NSAIDs in reducing the pain and stiffness of osteoarthritis, with the majority of studies reflecting short-term use compared with placebo and involving knee or hip joint osteoarthritis. There is no strong evidence to suggest a consistent benefit over paracetamol, although some people may obtain greater symptom relief from NSAIDs. No clinically important results about the effects of oral NSAIDs compared with opioids were found. All NSAIDs, irrespective of COX-1 and COX-2 selectivity, are associated with significant morbidity and mortality due to adverse effects on the gastrointestinal (GI), renal, and cardiovascular system.

The National Institute for Health and Clinical Excellence (NICE) investigated the efficacy and safety of NSAIDs (both standard and coxib) with respect to symptoms, function, quality of life, and adverse events in adults with osteoarthritis. Due to the large volume of data identified, only the key findings are summarized here. For information on the effect of oral NSAIDs compared with paracetamol, see Paracetamol. For information on the effect of oral NSAIDs compared with topical NSAIDs, see Topical NSAIDs.

Pain relief

Overall, the studies found that both standard NSAIDs and COX-2 inhibitors were superior to placebo in terms of reducing pain over treatment periods ranging from 6 weeks to 6 months. The majority of the data reported here are for pain measured on visual analogue scale (VAS) and WOMAC subscale. The limited data on direct comparisons of COX-2 inhibitors and non-selective NSAIDs suggested these two drug classes were equivalent. Only a small number of studies reported significant differences when comparing COX-2 inhibitors with standard NSAIDs.

Stiffness

Overall, the studies found that both standard NSAIDs and COX-2 inhibitors were superior to placebo in terms of reducing stiffness over treatment periods ranging from 15 days to 6 months. The majority of data reported here are for stiffness measured on VAS and WOMAC subscale. The limited data available indicated that COX-2 inhibitors and non-selective NSAIDs were comparable in terms of stiffness reduction. Only a small number of studies reported a significant difference when comparing COX-2 inhibitors with NSAIDs:

General function/global efficacy measures

Overall, both standard NSAIDs and COX-2 inhibitors were superior to placebo in terms of improving patients' and physicians' assessments of disease and overall function scores. The data on direct comparisons of COX-2 inhibitors and non-selective NSAIDs indicate that these two drug classes had similar effects for these outcomes. Outcomes were assessed using a number of measures including the Patients' and Physicians' Global Assessments and WOMAC. The treatment periods ranged from 15 days to 52 weeks. Only a small number of studies reported a significant difference on comparisons between two active drug interventions.

Physical function

Overall, both standard NSAIDs and COX-2 inhibitors were superior to placebo in terms of improving physical function. In general, data are presented for WOMAC. The treatment periods ranged from 6–14 weeks. The limited data on direct comparisons of COX-2 inhibitors and non-selective NSAIDs suggested these two drug classes may be comparable for this outcome.

GI safety

There are some data to suggest that certain COX-2 selective agents reduce the incidence of serious GI adverse events (such as perforations, ulcers, and bleeds) when compared with less selective agents, while the evidence for other agents has been more controversial. Dyspepsia, one of the most common reasons for discontinuation, remains a problem with all NSAIDs irrespective of COX-2 selectivity.

Cardiovascular safety

All NSAIDs have the propensity to cause fluid retention and to aggravate hypertension, although for certain NSAIDs this effect appears to be larger (e.g. etoricoxib). Increasingly, a pro-thrombotic risk (including myocardial infarction and stroke) has been identified with COX-2 selective agents in long-term studies, and there seems to be some evidence for a dose effect. These observational studies may demonstrate an increased cardiovascular risk from standard NSAIDs too. All NSAIDs may antagonize the cardioprotective effects of aspirin.

[National Collaborating Centre for Chronic Conditions, 2008]

There is a good amount of evidence from RCTs on the efficacy of paracetamol in people with osteoarthritis but trial data is mainly for people with osteoarthritis of the hip or knee. Paracetamol reduces pain in the short term compared with placebo, but appears to be less effective than oral standard or coxib nonsteroidal anti-inflammatory drugs (NSAIDs), especially in people with moderate-to-severe pain. Paracetamol can be used alone or in conjunction with other analgesics, although there is a limited quantity and quality of data on the efficacy of paracetamol used in combination with other analgesic drugs. Paracetamol is less likely than NSAIDs to cause gastrointestinal (GI) adverse events.

The National Institute for Health and Clinical Excellence (NICE) looked at studies on the efficacy and safety of paracetamol (compared with oral standard or coxib NSAIDs) for symptomatic relief from pain in adults with osteoarthritis. One Cochrane review and six additional studies were appraised. Five of these additional studies are not discussed further as there were high numbers of drop-outs in four of them, and one additional study [Fries and Bruce, 2003] just confirmed that the rates of serious GI adverse events increase with higher doses of paracetamol or ibuprofen, that the most serious problems occur in people at higher risk, and that little risk of serious GI toxicity has been found in over-the-counter use.

A Cochrane review (15 RCTs, n = 5986) assessed the efficacy and safety of paracetamol compared with placebo as well as both standard and coxib NSAIDs (celecoxib, diclofenac, ibuprofen, naproxen, and rofecoxib) for treating osteoarthritis (mainly of the hip or knee) [Towheed et al, 2006]. Literature searches were conducted up to July 2005.

Paracetamol compared with placebo: seven RCTs were found.

Paracetamol was superior to placebo in five of the seven RCTs. A pooled analysis of pain reduction (when resting, moving, sleeping, and overall) in the five trials was statistically significant, standardized mean difference (SMD) –0.13 (95% CI –0.22 to –0.04) but the clinical significance was inconclusive.

Assessment of pain, physical function, and stiffness using WOMAC scales found similar results for paracetamol and placebo.

When measuring pain on a visual analogue scale (0–100), pain relief with paracetamol decreased by 4 points more than placebo.

The NNT to improve pain ranged from 4–16.

Paracetamol compared with NSAIDs (both standard and coxibs): ten RCTs were found.

Paracetamol was less effective overall than NSAIDs in terms of: pain reduction; WOMAC pain, stiffness, function, and total scales; global assessments (both patient and investigator); and functional status.

NSAIDs were found to be significantly more effective than paracetamol for:

Pain at rest: three RCTs (n = 573): SMD –0.20 (95% CI –0.36 to –0.03) for ibuprofen 2400 mg, diclofenac, diclofenac plus misoprostol, celecoxib, naproxen. Four RCTs (n = 594): SMD –0.19 (95% CI –0.35 to –0.03) for ibuprofen 1200 mg, diclofenac plus misoprostol, rofecoxib 25 mg, naproxen.

Overall pain: eight RCTs (n = 2538): SMD –0.25 (95% CI –0.33 to –0.17) for ibuprofen 2400 mg, diclofenac, diclofenac plus misoprostol, celecoxib, naproxen. Seven RCTs (n = 1812): SMD –0.31 (95% CI –0.40 to –0.21) for ibuprofen 1200 mg, diclofenac plus misoprostol, rofecoxib 25 mg, naproxen.

The review found no significant differences between NSAIDs and paracetamol for pain on motion and Lequesne pain index, but NSAIDs were more effective than paracetamol in terms of: WOMAC pain, stiffness, function, and total scales; global assessments (both patient and investigator); and functional status.

People taking ibuprofen or naproxen (i.e. standard NSAIDs) compared with paracetamol were more likely to experience a GI adverse event, RR 1.47 (95% CI 1.08 to 2.00).

No significant difference was found overall between the safety of paracetamol and NSAIDs, although the median trial duration was only 6 weeks.

An RCT (n = 581) published subsequently of adults with mild-to-moderate osteoarthritis pain of the hip or knee randomized to receive paracetamol or naproxen, compared results in terms of safety or efficacy, over 6 or 12 months [Temple et al, 2006]:

WOMAC pain — no significant difference in treatment effect at 6 months between paracetamol and naproxen.

WOMAC stiffness — both groups of people taking paracetamol or naproxen had a similar outcome at 6 months.

WOMAC function — both groups of people taking paracetamol or naproxen had a similar outcome at 6 months.

Number of people with one or more adverse events — no significant difference in treatment effect at 6 months between paracetamol and naproxen.

Number of people with a serious adverse event — no significant difference at 6 months between paracetamol and naproxen.

Number of GI adverse events (constipation and peripheral oedema) — significantly less constipation and peripheral oedema at 6 months in people taking paracetamol compared with naproxen.

Number of withdrawals due to adverse events — no significant difference at 6 months between paracetamol and naproxen.

For information on the effect of paracetamol compared with opioid analgesics, see Opioid analgesics.

[National Collaborating Centre for Chronic Conditions, 2008]

Evidence to support the use of topical capsaicin is limited in terms of quality and quantity. No systematic reviews were found on the use of topical capsaicin in people with osteoarthritis, but evidence from four small RCTs found that short-term use of topical capsaicin was beneficial compared with placebo. Evidence from an economic evaluation of the use of topical capsaicin was also favourable in support of its use.

The National Institute for Health and Clinical Excellence (NICE) looked at studies that investigated the efficacy and safety of topical capsaicin compared with oral nonsteroidal anti-inflammatory drugs (NSAIDs) or placebo with respect to symptoms, function, and quality of life in adults with osteoarthritis.

Four RCTs (n ranging from 59–200) were appraised on topical capsaicin versus placebo (given four times daily) and focused on symptoms, function, and quality of life in people with osteoarthritis. All trials were parallel group studies and were considered methodologically sound. However, the site of osteoarthritis differed, and study duration varied from 4–12 weeks.

Topical capsaicin compared with placebo

In terms of:

Pain relief — with different outcomes, topical capsaicin was generally significantly more effective than placebo (with a trend towards being more effective the longer the treatment was used).

Reduction in morning stiffness — only one RCT reported on this and no significant difference was found between capsaicin and placebo.

Function outcomes — topical capsaicin was significantly more effective than placebo in grip strength (as measured by the percentage change from baseline).

Global assessment outcomes — topical capsaicin was significantly more effective than placebo.

Quality of life outcomes — only one RCT reported on this and no significant difference was found between capsaicin and placebo.

Adverse events:

One RCT (n = 59) reported that, over 9 weeks, 20 people (69%) using topical capsaicin for osteoarthritis of the hand had adverse events while 9 people (30%) using placebo had adverse events.

Four RCTs (n = 70, 59, 113, and 200) reported rates of withdrawals due to adverse effects — topical capsaicin compared with placebo: 3% vs. 14%; 14% vs. 23%; 20% vs. 11%; and 20% vs. 20%.

Economic evaluation

NICE looked at studies that conducted economic evaluations involving topical capsaicin.

An Australian study considered topical capsaicin compared with placebo and other drugs for people with osteoarthritis [Segal et al, 2004]. Data regarding the effectiveness of capsaicin was taken from the literature and the data were analysed in terms of the quality adjusted life year (QALY) gain.

Topical capsaicin was found to be cost effective compared with placebo, since it brings QALY gains at relatively low cost. In comparison to other drugs, topical capsaicin appeared likely to be closer to the cost of coxib NSAIDs, and significantly more expensive than some standard NSAIDs in a UK setting. However, some estimates do not include the adverse event costs of these drugs and given this, it is difficult to make reliable recommendations based on the Australian data.

There are limited data showing some positive effects from topical capsaicin, with short-term follow up. Although the evidence is limited to knee osteoarthritis, the NICE guideline development group were aware of widespread use in hand osteoarthritis as part of self-management, and felt that the data on efficacy at the knee could reasonably be extrapolated to the hand. No serious toxicity associated with capsaicin use has been reported in the peer-reviewed literature.

[National Collaborating Centre for Chronic Conditions, 2008]

There is some evidence that topical nonsteroidal anti-inflammatory drugs (NSAIDs) are more effective compared with placebo at improving short-term pain relief and function (up to 8 weeks) for people with osteoarthritis (mainly of the knee). There are limited data that compare the efficacy and safety of topical NSAIDs and oral NSAIDs in people with osteoarthritis, but topical NSAIDs may be as effective as oral NSAIDs at reducing pain in people with osteoarthritis of the knee. With respect to adverse effects, topical NSAIDs may be less likely than oral NSAIDs to cause gastrointestinal adverse effects in the first 12 weeks of use, although topical NSAIDs are associated with skin irritation. The RCT data do not allow a conclusive judgement on whether using topical NSAIDs reduces the incidence of serious NSAID-related adverse effects, but they seem to be preferred to using oral NSAIDs as early treatment for osteoarthritis, particularly for people who do not have widespread painful osteoarthritis. No data were found comparing the risks and benefits of topical NSAID use with paracetamol.

The National Institute for Health and Clinical Excellence (NICE) looked at studies that investigated the efficacy and safety of topical NSAIDs compared with oral NSAIDs or placebo with respect to symptoms, function, and quality of life in adults with osteoarthritis. Two systematic reviews and two additional RCTs on topical NSAIDs were appraised [Lin et al, 2004; Trnavsky et al, 2004; Niethard et al, 2005; Towheed, 2006].

Topical NSAIDs compared with placebo

A systematic review (13 RCTs, n = 1412) investigated the efficacy of topical NSAIDs compared with placebo in people with osteoarthritis [Lin et al, 2004]. Literature searches were performed up to July 2005.

Meta-analysis found that compared with placebo, topical NSAIDs:

Significantly reduced pain in weeks 1 and 2 (effect size 0.41, 95% CI 0.18 to 0.63, p < 0.05).

Did not significantly reduce pain in weeks 3 and 4 (effect size 0.08, 95% CI –0.04 to 0.2, p-value not reported).

As well as different drugs being used in the trials, there were also differences in the osteoarthritis site.

Another systematic review (four RCTs, n = 1412) investigated the efficacy and safety of topical diclofenac solution compared with placebo in people with osteoarthritis of the knee [Towheed, 2006]. Literature searches were performed up to February 2005.

Meta-analysis found that compared with placebo, over a mean of 8.5 weeks, topical diclofenac:

Significantly reduced WOMAC pain scores (SMD –0.33, 95% CI –0.48 to –0.18).

Significantly improved WOMAC stiffness scores (SMD –0.30, 95% CI –0.45 to –0.15).

Significantly improved physical function scores (SMD –0.35, 95% CI –0.50 to –0.20).

The first subsequent RCT (n = 50) investigated the efficacy and safety of ibuprofen 5% cream compared with placebo in people with osteoarthritis of the knee [Trnavsky et al, 2004].

Compared with placebo, topical ibuprofen cream was found to be statistically significantly better in terms of:

Pain at rest.

Pain on motion.

Overall pain.

Patient function.

Global assessment.

In terms of safety, no adverse events or withdrawals were reported in either group.

The second RCT (n = 238) investigated the efficacy of topical diclofenac gel compared with placebo in people with osteoarthritis of the knee [Niethard et al, 2005].

Compared with placebo, topical diclofenac gel was found to statistically significantly:

Reduce pain intensity.

Improve overall response.

Improve WOMAC scores.

Topical NSAIDs compared with oral NSAIDs

A systematic review (13 RCTs, n = 1412) investigated the efficacy of topical NSAIDs compared with oral NSAIDs in people with osteoarthritis [Lin et al, 2004]. Literature searches were performed up to July 2005.

An RCT (n = 622) compared topical diclofenac with oral diclofenac for 12 weeks.

Oral diclofenac significantly improved WOMAC function score compared with topical diclofenac.

There was no significant difference in WOMAC pain, WOMAC stiffness, or WOMAC physical function scores, or in patient global assessment.

The authors considered that there were no clinically relevant differences between the two treatments.

Topical diclofenac was found to be more favourable compared with oral diclofenac in terms of gastrointestinal and severe gastrointestinal adverse events. However, oral diclofenac was found to be more favourable compared with dry skin reactions and rash.

Meta-analyses comparing adverse events with topical NSAIDs versus oral NSAIDs found:

The rate ratio of local skin adverse reactions was significantly greater in people taking topical NSAIDs compared with oral NSAIDs.

No significant difference between oral and topical NSAIDs in the number of people with adverse events, GI adverse events, or central nervous system adverse events.

Additional RCT analyses were performed but their findings did not provide any further insight into differences in efficacy and safety between topical and oral NSAIDs.

Economic analyses

NICE evaluated studies that conducted economic evaluations involving topical NSAIDs. Comparing topical ibuprofen with oral ibuprofen, the NICE guideline development group concluded that:

In a population at low risk of adverse events, oral ibuprofen is likely to be a cost-effective treatment compared with topical ibuprofen.

In a higher risk population, treatment with topical ibuprofen is likely to be less expensive than treatment with oral ibuprofen.

[National Collaborating Centre for Chronic Conditions, 2008]

Evidence to support the efficacy of glucosamine for osteoarthritis is mixed, and any benefits are small. A Cochrane systematic review performed a meta-analysis of data from 20 RCTs: 17 trials compared glucosamine with placebo, and four trials compared glucosamine with a nonsteroidal anti-inflammatory drug (NSAID; ibuprofen in three trials and piroxicam in one trial). Sixteen RCTs evaluated the knee exclusively, two evaluated osteoarthritis at multiple sites, and two did not specify the location. When data from all studies were pooled, glucosamine was found to be more effective than placebo with respect to pain and function. However, subgroup analyses of the 10 RCTs in which allocation was adequately concealed, found that glucosamine was not more effective than placebo for relieving pain, stiffness, or function. Another subgroup analysis found that the glucosamine sulfate product made by the Rotta Pharmaceutical Company was more effective than placebo, while other glucosamine preparations (glucosamine sulfate and glucosamine hydrochloride) failed to show a benefit. The reasons for the differences in results are unknown, but may include differences in the products (there is no common standard for their manufacture), differences in the trial methods (e.g. different outcome measures), and differences in the methodological quality of the studies, including susceptibility to bias (most of the positive, and few of the negative, trials were funded by manufacturers of glucosamine). The health economics analysis conducted by the National Institute for Health and Clinical Excellence (NICE) concluded that glucosamine is not currently cost-effective for the NHS.

Sources of evidence

NICE looked at studies that investigated the efficacy and safety of glucosamine with respect to symptoms, function, and quality of life in adults with osteoarthritis. Due to the large volume of evidence found, trials with a sample size of less than 40 were excluded.

A Cochrane review and two additional RCTs published subsequently were appraised.

The Cochrane review (20 RCTs, n = 2596) investigated the effectiveness and safety of glucosamine in people with osteoarthritis [Towheed et al, 2005]. Literature searches were performed up to January 2005 and included osteoarthritis of different sites (16 RCTs used knee, two RCTs used multiple sites, and for two RCTs the site was not specified). All the trials included were of glucosamine sulfate, except one which was of glucosamine hydrochloride.

Glucosamine compared with placebo

Analyses including all the studies found that glucosamine reduced pain compared with placebo. However, analyses restricted to the RCTs with adequate allocation concealment found no significant difference between glucosamine and placebo in pain and WOMAC function scores. In two RCTs (n = 414), there was a statistically significant difference in minimum joint space width favouring glucosamine; but in one RCT (n = 212) there was no difference in mean joint space width.

In terms of safety, no significant difference in adverse events was found between glucosamine and placebo:

Number of participants reporting adverse events in 14 RCTs: RR 0.97 (95% CI 0.88 to 1.08).

Glucosamine compared with oral NSAIDs

Glucosamine was found to significantly reduce pain (measured on a visual analogue scale; VAS) compared with NSAIDs in people with osteoarthritis of the knee:

Summary pooled standardized mean difference (SMD) in three RCTs: –0.40 (95% CI –0.60 to –0.19).

Regarding harms, glucosamine was less likely than NSAIDs to produce adverse reactions:

Number of participants reporting adverse events in four RCTs: RR 0.29 (95% CI 0.19 to 0.44).

One RCT published subsequently compared four interventions (glucosamine hydrochloride [1500 mg/day], chondroitin sulfate [1200 mg/day], combined chondroitin sulfate with glucosamine hydrochloride, and placebo) over 24 weeks in people (n = 1583) with osteoarthritis of the knee [Clegg et al, 2006].

No significant difference was found between glucosamine and placebo in the proportion of people with a 20% decrease in WOMAC pain score at 24 weeks.

A second RCT in people (n = 325) with osteoarthritis of the knee compared glucosamine sulfate (1500 mg/day), paracetamol, and placebo in a 6-month treatment phase [Herrero-Beaumont et al, 2007].

Significant changes were found in favour of glucosamine sulfate compared with placebo in terms of the Lequesne Index and WOMAC function scores.

When economically evaluating the role of glucosamine, the NICE Guideline Development Group concluded that:

For glucosamine sulfate, evidence to support its efficacy was not strong enough to warrant recommending that it should be prescribed on the NHS.

For glucosamine hydrochloride, evidence to support its efficacy as a symptom modifier was poor and, because only one product is licensed, it would not be cost effective to prescribe glucosamine on the NHS — NICE regarded measurement of joint-space narrowing as of questionable value.

[National Collaborating Centre for Chronic Conditions, 2008]