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Everybody has experienced pain at some point, and it is safe to say that it is not a pleasant sensation.
At the most basic level, any pain takes its origin from local tissue injury. Following tissue injury, there is a release of locally synthesized inflammatory mediators (prostaglandins, leukotrienes, interleukins, bradykinin, serotonin) that stimulate the free nerve endings.
These nerves transmit the information to your brain, which tags the sensory component to an emotional experience called pain.
Pain can be acute, and a one-time experience, such as a headache, or it can be recurring and quite debilitating, such as pain in rheumatoid arthritis.
Chronic pain is defined as pain that lasts longer than the usual course of an acute injury or disease, or pain that recurs for months or years.
A study on the global burden of chronic pain noted at least 10% of the world’s population is affected by a chronic pain condition and every year an additional 1 in 10 people develop chronic pain. (1)(2)
According to the American Academy of Pain Medicine, in the USA, pain affects more Americans than diabetes, heart disease, and cancer combined. With all this data on the burden of pain, it is not surprising why pain is debatably considered a “disease.” (1)(2)
What are Analgesics?
Analgesics, or pain killers, are a group of agents that relieve pain due to inflammation.
There are two main types of oral analgesics:
- Non-steroidal anti-inflammatory drugs (NSAIDs)/Non-narcotic
NSAIDs relieve the pain carried by nerve endings (sensory component), whereas opioid analgesics reduce the sensory and emotional components of pain.
NSAIDs are effective for superficial pain originating from the skin, muscles, and joints, whereas opioids work more effectively to numb pain arising from deeper organs.
How do Analgesics Act?
Local tissue injury releases prostaglandins. Prostaglandins have two major actions:
- Sensitize pain receptors and lower the threshold for painful stimuli
- Intensify the activation of the nerve endings by other inflammatory mediators such as bradykinin, serotonin, and histamine
NSAIDs work by inhibiting the production of prostaglandins by inhibiting two types of cyclooxygenase enzymes:
COX-1 is present in all cells, while COX-2 is induced in the presence of inflammation.
|COX-1 Inhibition||COX-2 Inhibition|
|Prevents platelet aggregation|
Traditional NSAIDs inhibit both COX enzymes and thus relieve pain, reduce fever, and inflammation. Selective COX-2 inhibitors (coxibs) inhibit the COX-2 enzyme primarily and thus exerts anti-inflammatory effects.
Acetaminophen, or paracetamol, acts by a different mechanism by inhibiting the COX-3 enzyme in the brain. It produces analgesia by altering the pain perception in the brain but has a little anti-inflammatory effect.
Opioid analgesics act on the mu-opioid receptors on the nerves in the periphery, spinal cord, and brain and reduce their excitability, in addition to preventing the transmission of pain signals.
Types of Oral Analgesics
|Types of Analgesics|
|COX-2 selective inhibitors||Celecoxib|
Benefits of Analgesics
According to the WHO pain relief ladder, acetaminophen and NSAIDs are the first recommendation for the initial management of pain. If found ineffective, opioids can then be prescribed. (3)
Acetaminophen is the first drug of choice for the treatment of mild to moderate pain due to its safety and tolerability. (4)
Some of the special features of acetaminophen are:
- No gastric irritation
- No rise in blood pressure
- Safe to use in pregnancy (category B drug)
- Safe to use in impaired renal function
- Recommended for use in viral infections in the pediatric group
Like acetaminophen, aspirin is also effective in acute mild to moderate pain. The dose range is between 500 mg and 1200 mg, and higher doses are more effective at pain relief. Aspirin 1000 mg is comparable to oral sumatriptan 50 mg for acute migraine pain.
However, like NSAIDs, aspirin causes gastric irritation that can lead to bleeding ulcers. Also, people with diagnosed urticaria or asthma may suffer severe bronchospasm as a hypersensitivity reaction to aspirin. (5)
Aspirin also offers other benefits to its use:
- Regular use of aspirin is associated with a reduced risk of colon and rectal cancers.
- Low doses of aspirin suppress polyp development in familial colonic polyposis.
- Aspirin lowers the risk and retards the progression of Alzheimer’s disease.
- Aspirin has shown benefit in hypertension in pregnancy (preeclampsia) by suppressing thromboxane A2.
- Premedication with aspirin reduces niacin-induced allergic reaction.
3. Traditional NSAIDs/non-selective COX inhibitors
Traditional NSAIDs inhibit both types of COX enzymes and thus produce anti-inflammatory and analgesic effects. They are more effective at reducing pain associated with concomitant inflammation, such as osteoarthritic pain and dysmenorrhea.
An increase in the dose produces greater anti-inflammatory effects but also increases the adverse effects. Most NSAIDs are equally effective, and the choice depends upon the dosing schedule and safety profile.
NSAIDs are more effective than acetaminophen for primary dysmenorrhea and osteoarthritis. However, they are associated with a higher incidence of adverse effects, such as headache, drowsiness, nausea, and indigestion.
4. COX-2 selective NSAIDs
The advantage of COX-2 selective inhibitors is they produce analgesic and anti-inflammatory effects without the gastrointestinal adverse effects experienced with traditional NSAIDs.
COX-2 selective NSAIDs are considered second-line medications for mild to moderate pain because they have similar effectiveness to non-selective NSAIDs but come at a higher cost.
Celecoxib is currently the only COX-2 selective NSAID approved in the United States for bone or dental pain, dysmenorrhea, headache, and arthritis.
Adverse effects include an increased risk of cardiovascular events (stroke, heart attack, thrombotic events).
5. Opioid analgesics
Morphine is a potent opioid analgesic that can be used alone if opioids combined with acetaminophen or NSAIDs fail to relieve moderate to severe pain. The distress and anxiety associated with deep-seated pain, such as in a heart attack or trauma, are reduced.
Although the use of oral morphine plays a role in the treatment of chronic pain, the oral narcotic treatment of acute pain most often involves hydrocodone and oxycodone.
Opioids should be used cautiously because of the risk of addiction, even with short-term use.
Tramadol has a dual-action – it works on the opioid receptor and inhibits the uptake of norepinephrine and serotonin. It is most often used to treat postoperative or neuropathic pain.
Because of its inferior efficacy and no clear benefit regarding safety compared with other alternatives, tramadol should not be a first-line oral analgesic. (7)
The advantages of tramadol over morphine include:
- Less respiratory depression
- Low tolerance or dependence
Side Effects of Analgesics
Common side effects
|Side Effects of Analgesics|
|Traditional NSAIDs||Gastric bleeding|
|COX-2 selective inhibitors||Renal dysfunction|
Long-term ingestion of non-opioid analgesics has been linked to renal dysfunction in susceptible patients with preexisting kidney disease. Typically, it occurs in the mid or older age group with a positive history of chronic pain and regular analgesic use over months to years.
Most evidence points to an association with phenacetin or its metabolite paracetamol in combination with aspirin or caffeine.
Prostaglandin E2 is said to have protective vasodilatory effects on the kidney and is not produced due to the inhibitory action of NSAIDs on the cyclooxygenase enzyme.
Safe analgesics to use in kidney disease
The American Geriatric Society recommends avoiding the chronic use of all oral NSAIDs, including high-dose aspirin, in the elderly >75 years.
Acetaminophen is primarily metabolized extensively in the liver. Only 2%-5% of the dose is excreted unchanged in the urine, and there are no reported significant changes observed in patients with kidney failure.
Tips for Taking Analgesics
- Gastric irritation with NSAID use can be prevented by combining it with antihistamines, misoprostol 800 mg, or proton-pump inhibitors.
- Always read the maximum recommended dosage on the package insert.
- Start analgesics on the lowest possible dose and for the shortest duration.
- Aspirin can cause an allergic reaction in those suffering from asthma.
- Opioid-induced vomiting can be avoided by preoperative diagnosis and treating it with antihistamine or serotonin antagonists.
- Opioid-induced slowing of bowel movement can be treated with metoclopramide.
|Recommended Dosage of Commonly Used Analgesics|
|Acetaminophen/paracetamol||500 mg thrice daily (daily max 4 g)|
|Aspirin||300-600 mg thrice daily|
|Ibuprofen||400 mg thrice daily|
|Naproxen||250 mg twice daily|
|Celecoxib||100-200 mg twice daily|
- Avoid taking other anticoagulant medications with aspirin as it can cause increased bleeding tendency.
- Alcohol, barbiturates, and antipsychotic drugs will increase the sedative effect of opioid agents.
- All NSAIDs should be used carefully in patients with preoperative diagnosis-existing disease conditions, such as peptic ulcer disease, hypertension, liver disease, and kidney disease.
- Opioids are recommended as a step-up from NSAIDs for moderate to severe pain. Their use can lead to serious long-term effects such as tolerance and dependence.