Pharmacology of commonly used drugs in musculoskeletal
disorders
Mr. Harish Kurup
Consultant in Orthopaedics
Pilgrim Hospital, Boston
Paracetamol / Acetaminophen
Paracetamol (called acetaminophen in the USA) is a derivative of p-aminophenol,
which corresponds to the active principal metabolite phenacetin. Paracetamol inhibits
prostaglandin biosynthesis in the central nervous system but hardly in the peripheral
tissues. Paracetamol only has minimal anti-inflammatory action compared to nonsteroidal anti-inflammatory agents.
Indications
Paracetamol has good analgesic and antipyretic properties. It is suitable for the
treatment of pain from any orthopaedic pathology and is usually the first line drug. In
general, Paracetamol is less efficacious than salicylates and other antirheumatic
agents for problems that require anti-inflammatory treatment.
Paracetamol is well suited for use in children. Paracetamol appears to have little
potential for dependence. Paracetamol is safe in pregnancy and lactation.
Adverse reactions
Paracetamol only rarely causes gastrointestinal problems or allergic skin reactions.
Blood dyscrasia (e.g. thrombocytopenia), and haemolytic anaemia are very rare. A
minority of the responds to Paracetamol with bronchospasms. It is not safely
established if Paracetamol can cause a nephropathy, like drug combinations
containing phenacetin.
When metabolized in the liver, small amounts of an intensely active metabolite, which
is normally immediately inactivated by glutathione, are produced. An overdose causes
a glutathione deficiency; the reactive metabolite may then cause hepatocellular
damage and necrosis leading to acute liver failure. Toxic effects have been observed
in adults treated with doses of more than 10 g (20 tablets). However, if there is a preexisting liver insufficiency, Paracetamol can be hepatotoxic even in small amounts.
The antidote N- acetyl cysteine must be administered within 8 to 10 hours when there
is intoxication.
Contraindications
Hypersensitivity to Paracetamol.
NSAID
Non-steroidal anti-inflammatory drugs
Ibuprofen and Diclofenac are the most commonly used NSAIDs.
Ibuprofen
Ibuprofen, a non-steroidal anti-inflammatory agent belonging to the group of
propionic acid derivatives, inhibits the enzyme cyclo-oxygenase (prostaglandin
synthesis) which catalyzes the transformation of unsaturated fatty acids to
prostaglandins. The inhibition of the prostaglandin synthesis is the mechanism for the
analgesic, antipyretic, and anti-inflammatory action of the drug.
Indications
Ibuprofen is suited for the treatment of pain, in particular of pain related to the
musculoskeletal system. Pain accompanying arthritis can be reduced and the mobility
of the joints can be increased. Non-steroidal anti-inflammatory agents only have a
symptomatic effect on joint diseases; the development of the disease is not
significantly influenced. In average, ibuprofen has proven equally as efficient as other
anti-inflammatory drugs in all areas of application (e.g. diclofenac, indomethacin, and
naproxen).
Adverse reactions
Ibuprofen predominantly causes gastrointestinal problems (dyspepsia, nausea,
vomiting, epigastric pain, rarely diarrhoea or constipation). According to different
studies, ibuprofen seems to cause fewer such side-effects than many other antiinflammatory agents. Dangerous complications (bleeding ulcers, perforations) are not
common.
Anti-inflammatory drugs have other side-effects like vertigo, headaches, skin rashes,
increase of liver enzymes, etc. Dangerous renal complications (water and salt
retention, acute renal failure), hepatitis, and general hypersensitive reactions (fever,
hypertension, and aseptic meningitis) are rare.
Contraindications
Hypersensitivity to aspirin (acetylsalicylic acid) or other non-steroidal antiinflammatory agents.
Active peptic ulcer.
Safe in pregnancy (avoid in the last 3 months – can cause premature closure of ductus
arteriosus)
Diclofenac
Like other non-steroidal anti-inflammatory agents, diclofenac, a phenylacetic acid
derivative, inhibits the prostaglandin biosynthesis.
Indications
The efficacy of Diclofenac as an anti-inflammatory agent and analgesic is well
documented: in comparison with many other anti-inflammatory agents (e.g. ibuprofen,
indomethacin, naproxen, piroxicam) Diclofenac has proven to be about equal. Like
other non-steroidal anti-inflammatory agents, Diclofenac only produces a
symptomatic effect. Diclofenac is available in both oral and paraenteral forms.
Diclofenac is also available in ointments and gels.
Adverse reactions
Diclofenac causes gastrointestinal problems (upper abdominal and gastric pain,
nausea, vomiting, diarrhoea or constipation) in more than 5% of the treated subjects.
Headaches, vertigo and sleep disturbances are also observed occasionally.
Haematological problems (e.g. granulocytopenia), increased liver enzymes,
exanthemas and renal function disorders are less frequent.
Dangerous reactions such as bleeding gastric ulcers, perforations, hepatitis and renal
failure are rare.
Patients with pre-existing heart failure, hypertension or renal failure are more prone to
the development of renal function disorders and should be observed closely after the
beginning of the treatment.
Contraindications
Active gastric or duodenal ulcers. Aspirin intolerance. All NSAIDs are better avoided
in third trimester of pregnancy.
Codeine
Codeine is an opioid (methylmorphine) with a relatively limited analgesic effect; it
does not cause significant respiratory depressions. In most humans 10% of a codeine
dose is transformed to morphine through demethylation in the liver.
Indications
Codeine is suitable for the treatment of mild and moderate pain. A minority of the
population does not respond to the analgesic effect. Codeine can be combined
advantageously with non-opioid analgesics. Aspirin (500 mg), Paracetamol (500 mg),
or other more recent non-steroidal anti-inflammatory agents can be suitably combined
with codeine (30 mg).
Adverse reactions
In many cases the imperative constipating effect of codeine is undesired and it is often
a reason against long-term use of the drug. Vomiting and nausea also occur regularly.
All the other opioid side-effects are also present with codeine but they are
comparatively mild. Retention of urine, itching, vertigo, palpitations or bradycardia,
sweating, and mild central nervous effects (sedation, mood changes, and some
hallucinations) have been observed.
A respiratory depression under therapeutic doses is very rare. There is a danger of
addiction for subjects with a former or present dependence of the opioid type.
Contraindications
Advanced respiratory insufficiency, bronchial asthma, raised intracranial pressure.
Better avoided in late stages of pregnancy and young children.
Morphine
Morphine is the principal medical alkaloid of opium. Its effect at the µ-receptors in
the central nervous system is said to be responsible for analgesia, euphoria,
dependence potential and respiratory depressions. Morphine also binds with kreceptors which mediate spinal analgesia, miosis and sedation.
Indications
Morphine still is the drug of choice for the treatment of severe acute or chronic pain.
It is mostly used parenterally for acute pain (multiple injuries, post-operative).
Morphine is also frequently injected to prepare for surgery and it can also be given
during the operation for the suppression of nociceptive stimuli.
Adverse reactions
Morphine causes a wide range of side-effects. However, severe reactions such as
respiratory depressions and pronounced hypotension are uncommon when the drug is
used therapeutically. Drop in blood pressure due to a cardiac infarction or
hypovolemia can have dangerous results.
Constipation is the most important problem in long-term treatment. Even therapeutic
doses can reduce respiratory frequency and can cause oliguria or urinary retention.
Further potential side-effects are euphoria and dysphoria, anxiety, pruritis, urticaria,
bronchospasms, spasms of the sphincter oddi, oedemas, headaches and miosis.
Development of tolerance entails ever-increasing doses.
Naloxone is used for reversing the respiratory depression caused by Opiods.
Contraindications
Advanced respiratory insufficiency, raised intracranial pressure.
Steroids for injection
(Also read chapter on injection techniques)
Corticosteroids are hormones that are produced naturally by the adrenal glands. They
have many important functions in the body, including control of inflammatory
responses. Corticosteroid medicines are man-made derivatives of the natural
hormones.
Triamcinolone
Triamcinolone is a synthetic steroid that has an anti-inflammatory effect. It is the most
common choice for joint injection.
Local complications:
- may cause fat necrosis and loss of skin pigmentation
- In some cases may accelerate joint degeneration
- systemic absorption may occur from intra-articular injection
- absorption is increased by usage of water soluble preparations, dose injected,
and injection into multiple joints
- may cause transient hyperglycemia in diabetic patients (and therefore is
advised in type I or brittle diabetics)
- avascular necrosis of the femoral head is a rare complication
- iatrogenic septic arthritis is uncommon problem but it does occur, so all joint
injections should be performed using sterile technique, with a formal betadine prep
and use of sterile gloves
Triamcinolone Preparations for Intra-articular Injection
Triamcinolone hexacetonide (Aristospan)
- Used for large joints
- has a tendency to cause skin atrophy and hypopigmentation
- has a long lasting effect
Triamcinolone acetonide (Kenalog)
- Used for small and medium sized joints
- small joint might receive 10 mg of Kenalog, and larger joints 40 mg
Glucosamine
Glucosamine is an amino sugar and a prominent precursor in the biochemical
synthesis of glycosylated proteins and lipids. Glucosamine is one of the most
abundant monosaccharides. It is produced commercially by the hydrolysis of
crustacean exoskeletons or, less commonly by fermentation of a grain such as corn or
wheat. In body glucosamine forms the precursor of glycosaminoglycans,
proteoglycans, and glycolipids.
Oral glucosamine is commonly used for the treatment of osteoarthritis. Since
glucosamine is a precursor for glycosaminoglycans, and glycosaminoglycans are a
major component of joint cartilage, supplemental glucosamine may help to rebuild
cartilage and treat arthritis. Its use as a therapy for osteoarthritis appears safe, but
there is conflicting evidence as to its effectiveness. A Cochrane review in 2005 has
found no advantage of glucosamine over placebo in treatment of arthritis.
The possible effects of glucosamine sulfate in patients with osteoarthritis may be the
result of its anti-inflammatory activity, the stimulation of the synthesis of
proteoglycans and the decrease in catabolic activity of chondrocytes inhibiting the
synthesis of proteolytic enzymes and other substances that contribute to damage
cartilage matrix and cause death of articular chondrocytes.
Clinical use
Commonly sold forms of glucosamine are glucosamine sulfate and glucosamine
hydrochloride. A typical dosage of glucosamine salt is 1,500 mg per day.
Glucosamine is often sold in combination with other supplements such as chondroitin
sulfate and methylsulfonylmethane.
Safety
Clinical studies have consistently reported that glucosamine appears safe. Since
glucosamine is usually derived from shellfish, those allergic to shellfish may wish to
avoid it. It does not interfere with control of diabetes.
Chondroitin sulphate
Chondroitin sulfate is a sulfated glycosaminoglycan (GAG) composed of a chain of
alternating sugars (N-acetylgalactosamine and glucuronic acid). It is usually found
attached to proteins as part of a proteoglycan. Chondroitin sulfate is an important
structural component of cartilage and provides much of its resistance to compression.
The benefit of chondroitin sulfate in patients with osteoarthritis is likely the result of a
number of effects including its anti-inflammatory activity, the stimulation of the
synthesis of proteoglycans and hyaluronic acid, and the decrease in catabolic activity
of chondrocytes inhibiting the synthesis of proteolytic enzymes, nitric oxide and other
substances that contribute to damage cartilage matrix and cause death of articular
chondrocytes
Clinical use
Chondroitin is an ingredient found commonly in dietary supplements used as an
alternative medicine to treat osteoarthritis. Chondroitin appears to be made from
extracts of cartilaginous cow and pig tissues (cow trachea and pig ear and nose), but
other sources such as shark, fish and bird cartilage are also used.
Safety
Clinical studies have not identified any significant side effects or overdoses of
chondroitin sulfate, which supports its long-term safety.