Glucosamine

Glucosamine occurs naturally in all human tissues. It stimulates the synthesis of glycosaminoglycan, proteoglycan and hyaluronic acid, although the precise mechanism of action remains to be established. Formulated as glucosamine sulphate (Dona® and various others), glucosamine has been evaluated for its efficacy in relieving the symptoms of osteoarthritis and its disease-modifying potential.

In two large randomised, double-blind, multicentre studies in patients with osteoarthritis, oral or intramuscular glucosamine for 4–6 weeks was associated with a greater decrease in symptom severity (as assessed by the Lequesne index) than placebo. In addition, there was a greater proportion of responders (defined as patients with a ≥3-point reduction in the Lequesne index, along with a positive overall assessment by the investigator) at the end of the treatment period with glucosamine than with placebo. In two large 4-week trials, oral glucosamine produced similar improvements to ibuprofen in the Lequesne index in one study and in articular pain scores in the other study. In a smaller 8-week comparative trial, oral glucosamine therapy achieved a significantly greater improvement in articular pain score than ibuprofen, and the investigators rated treatment efficacy as ‘good’ in a significantly greater proportion of glucosamine than ibuprofen recipients. In comparison with piroxicam, glucosamine significantly improved arthritic symptoms after 12 weeks of therapy and remained effective 8 weeks after treatment was discontinued.

Beneficial effects of long-term oral glucosamine therapy in preventing joint space narrowing and improving symptoms were shown in two 3-year placebo-controlled trials in a total of 414 patients with osteoarthritis. Statistically significant differences favouring glucosamine were noted in the per-protocol and intention-to-treat analyses for the primary endpoints for both joint structural changes and symptom modification.

Glucosamine has a tolerability profile similar to that of placebo and is better tolerated than ibuprofen or piroxicam. In particular, glucosamine recipients had a markedly lower incidence of gastrointestinal disturbances than those receiving ibuprofen. Other adverse events reported in both glucosamine and ibuprofen recipients were pruritus or skin reactions, flushing and fatigue. In general, a lower incidence of withdrawal from clinical trials was reported for glucosamine recipients than either ibuprofen or piroxicam recipients.

Glucosamine sulphate is a formulation of the salt of D-glucosamine, the active component, combined with sulphuric acid. Glucosamine also occurs naturally in all human tissues. This agent has a particular affinity for cartilaginous tissue, where it is readily incorporated into proteoglycan and glycosaminoglycan macromolecules which form the cartilage matrix.

Although its mechanism of action yet unclear, endogenous or exogenously administered glucosamine is thought to be involved in the synthesis of glycosaminoglycans, proteoglycans and hyaluronic acid, which are components of cartilage and synovial fluid.

In vivo, glucosamine was more effective in reducing inflammation in the rat paw induced by nonspecific inflammatory agents (carrageenan, dextran and formalin) than inflammation induced by specific mediators of inflammation (bradykinin, serotonin and histamine); it was less potent than aspirin (acetylsalicylic acid) for all of the inflammatory agents tested. Glucosamine is also mildly effective in inhibiting proteolytic enzymes in vivo. It effectively inhibits lysosomal enzymes and the generation of Superoxide radicals in vitro, although lower concentrations of indomethacin achieve the same effect.

The anti-inflammatory effects of glucosamine are most likely cyclo-oxygenase independent; glucosamine has no inhibitory effect on prostaglandin biosynthesis. In addition, glucosamine is unable to inhibit phenylquinone-induced writhing in mice, suggesting a lack of analgesic activity.

The pharmacokinetic evaluation of glucosamine nas been limited by a number of difficulties, which include the rapid utilisation of glucosamine in vivo, insensitive assay methods and the ethical and technical limitations associated with administering radioactively labelled [¹⁴C] glucosamine to humans.

Glucosamine is rapidly absorbed after oral administration and has a bioavailability of 26%, whereas intramuscularly administered glucosamine has a bioavailability of 96%. [¹⁴C] Glucosamine was administered either orally (250mg), intravenously (400mg) or intramuscularly (400mg) to two volunteers each: maximum plasma concentrations (C_max) were 31, 128 and 130 µmol/L, respectively. C_max was reached within 8–10 hours of administration.

The radioactivity from [¹⁴C] glucosamine is initially distributed in the plasma and binds to plasma globulins. It then rapidly diffuses into the tissues and organs according to a two-compartment model, with the highest concentrations found in the liver and kidney and notable concentrations found in the articular cartilage and bone.

Glucosamine sulphate dissociates into D-glucosamine and a sulphate ion. The active component D-glucosamine is metabolised into carbon dioxide, water and urea. The elimination half-life (t1/2) of D-glucosamine was approximately 70 hours after oral and intravenous administration of [¹⁴C] glucosamine in healthy volunteers. Intramuscularly administered glucosamine had a t1/2 of 57 hours.

Faecal excretion of radioactivity accounted for less than 1% of an intravenously or intramuscularly administered dose. Approximately 11 % of the radioactivity from oral glucosamine was excreted in the faeces 24–72 hours after administration. Urinary excretion of radioactivity was highest after intramuscular administration: 37% of the administered dose was recovered in the urine and faeces compared with 28% and 21% of intravenous and oral glucosamine, respectively.

No data are available on the pharmacokinetic profile of glucosamine in elderly patients and patients with hepatic or renal impairment.

In short-term clinical trials, oral or intramuscular glucosamine has been evaluated in comparison with placebo and the NSAIDs ibuprofen and piroxicam for the symptomatic relief of osteoarthritis of the knee. It has also been compared with placebo for its disease-modifying potential in long-term trials.

In comparison with placebo, glucosamine significantly improved osteoarthritis in two large randomised double-blind trials where it was administered either orally for 4 weeks or intramuscularly for 6 weeks. An improvement was reflected by a significantly greater decrease in the Lequesne index (used to measure symptom severity) and a significantly greater proportion of responders (defined as patients with a ≥3-point reduction in the Lequesne index, along with a positive overall assessment by the investigator) at the end of the treatment period. This improvement was also reflected in a smaller study which showed that a greater proportion of glucosamine recipients had an improvement in joint pain, tenderness and swelling than placebo recipients. One study demonstrated that glucosamine was also significantly more effective than placebo in relieving pain and functional parameters for osteoarthritis of the spine.

Oral glucosamine had similar efficacy to ibuprofen in two large 4-week studies and was significantly better in a smaller 8-week study. Both glucosamine and ibuprofen showed similar improvements in the Lequesne index and articular pain in the larger trials. In the smaller study, a significantly greater proportion of glucosamine recipients had an improvement in articular pain score, and investigators rated treatment efficacy as ‘good’ in a significantly greater proportion of glucosamine- than ibuprofen-treated patients. In a further trial, oral glucosamine for 12 weeks significantly improved arthritic symptoms compared with either piroxicam or placebo. This improvement was maintained 2 months after glucosamine treatment was discontinued, an effect that was not seen with piroxicam therapy.

Two large, randomised, double-blind, placebo-controlled studies have been published evaluating oral glucosamine for its disease-modifying potential in a total of 414 patients with osteoarthritis. After 3 years of glucosamine therapy, both studies showed symptomatic improvement and no appreciable narrowing of joint space. In contrast, placebo recipients demonstrated joint space narrowing in both trials, with concomitant worsening of symptoms in one of the studies. Statistically significant differences favouring glucosamine were noted in the per-protocol and intention-to-treat analyses for the primary endpoints for both joint structural changes and symptom modification in both studies.

Glucosamine was generally well tolerated in clinical trials; it had a tolerability profile similar to that of placebo and was better tolerated than ibuprofen or piroxicam. Over a 4- to 6-week period there were no statistically significant differences between the types and incidence of adverse events reported for glucosamine and placebo recipients. All adverse events were transient in nature and mild to moderate in severity. After oral administration of glucosamine 1.5 g/day, gastrointestinal disturbances, pruritus or skin reactions, and headaches were reported with a similar incidence to those with placebo. The incidence of local reactions, nausea and vomiting was similar for intramuscular glucosamine (0.4g twice weekly) and placebo. Pain or oedema of the legs and pruritus or skin reactions occurred only in glucosamine recipients. Long-term comparisons also showed no important differences between the tolerability profiles of glucosamine and placebo.

Glucosamine had a significantly better tolerability profile than either ibuprofen or piroxicam. Gastrointestinal symptoms, pruritus or skin reactions, and flushing or fatigue were more commonly reported with ibuprofen than glucosamine. In addition, a greater number of ibuprofen recipients withdrew from further study because of adverse events. Significantly fewer adverse events were reported and the incidence of withdrawal from treatment (for any reason) was significantly lower with glucosamine than with piroxicam.

Glucosamine is available as both an oral and an intramuscular formulation. Oral administration of two 250mg glucosamine tablets or capsules is recommended three times daily, preferably with meals. Treatment should be continued for 6 weeks or longer if necessary. Glucosamine is also formulated as a powder (1500mg per sachet) which should be dissolved in a glass of water before administration, and given once daily with meals for 4–12 weeks or longer if necessary. The dosage of intramuscular glucosamine is 400 or 800mg three times weekly for 4–6 weeks, or longer if required. It is recommended that glucosamine therapy is repeated at intervals of 2 months or when symptoms recur.

Glucosamine is contraindicated in patients with a hypersensitivity to glucosamine sulphate. The oral formulation contains aspartame and is therefore not recommended in patients with phenylketonuria. Intramuscularly administered glucosamine contains lidocaine and is contraindicated in patients with arrhythmias or acute heart failure and in patients hypersensitive to lidocaine.

At present there have been no studies in patients with renal or hepatic impairment, and administration of glucosamine to these patients should be under medical supervision.

Steroidal or nonsteroidal analgesic or anti-inflammatory agents can be coadministered with glucosamine.