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8 Nonsteroidal Anti-inflammatory Drugs

8 Nonsteroidal Anti-inflammatory Drugs
The Massachusetts General Hospital Handbook of Pain Management

8
Nonsteroidal Anti-inflammatory Drugs

Jane Ballantyne

Take an aspirin and call me in the morning.
—Twentieth-century physician

I. Pharmacology
II. Adverse effects and contraindications

1. Gastrointestinal effects

2. Decreased hemostasis

3. Surgical bleeding

4. Renal dysfunction and failure

5. Drug interactions

6. Other adverse effects
III. New NSAIDs

1. Differential inhibition of cyclooxygenase isoenzymes

2. New stereoisomers

3. Central nervous system activity

4. Other approaches
IV. NSAID use in specific populations

1. Perioperative patients

2. Chronic noncancer pain patients

3. Cancer patients
V. Conclusion
Selected Reading

The nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, are the most widely used analgesics in the United States and worldwide. Traditionally considered to be weak analgesics, they have achieved popularity as treatment for headaches, menstrual cramps, arthritis, and a wide range of minor aches and pains. Recently, NSAIDs have also become popular for use in the surgical population, especially since the advent of injectable preparations. Because of their predominantly peripheral site of action, they are used in combination with opioids and other centrally acting analgesics, and they are used in combination therapies for severe pain, both acute and chronic. In pain clinics, NSAIDs are often underutilized because of their inadequacy as a sole therapy for severe pain; their potential for providing useful adjunctive analgesia is easily forgotten. This chapter reviews the use of NSAIDs for acute and chronic pain: indications, efficacy, side effects, and contraindications.
I. PHARMACOLOGY
The NSAIDs are a heterogeneous group of compounds consisting of one or more aromatic rings connected to an acidic functional group (Fig. 1). The chemical families of commonly used NSAIDs are outlined in Table 1. The NSAIDs are weak organic acids (pKa 3 to 5.5), act mainly in the periphery, bind extensively to plasma albumin (95% to 99% bound), do not readily cross the blood–brain barrier, are extensively metabolized by the liver, and have low renal clearance (<10%).

Figure 1. Chemical structures of commonly used nonsteroidal anti-inflammatory drugs.

Table 1. Classification of commonly used antipyretic analgesics

Acetaminophen is not strictly an anti-inflammatory drug, but it is included because it shares many of the properties of the NSAIDs. In contrast to the true NSAIDs, it is nonacidic and a phenol derivative, and it readily crosses the blood–brain barrier. Its action resides mainly in the central nervous system, where prostaglandin inhibition produces analgesia and antipyresis. Its peripheral and anti-inflammatory effects are weak.
NSAIDs are powerful inhibitors of prostaglandin synthesis through their effect on cyclooxygenase (COX) (Fig. 2). Prostaglandins have many effects, and the therapeutic and toxic effects of NSAIDs can be accounted for by their ability to inhibit prostaglandin and thromboxane synthesis (Table 2). Prostaglandins themselves are not thought to be important pain mediators, but they do cause hyperalgesia by sensitizing peripheral nociceptors to the effects of various mediators of pain and inflammation, such as somatostatin, bradykinin, and histamine. Thus, NSAIDs are used primarily to treat hyperalgesia or secondary pain, particularly pain resulting from inflammation.

Figure 2. A schematic diagram showing the metabolism of phospholipids and arachidonic acid. NSAIDs inhibit cyclooxygenase and thereby suppress the synthesis of prostaglandin E, prostacyclin, and thromboxane, altering the balance between these eicosanoids and the leukotrienes.

Table 2. Prostaglandin and thromboxane actions

In the last decade, two isoforms of COX have been recognized. An inducible isoenzyme (COX-2), in addition to the constitutive enzyme (COX-1), has been identified. COX-1 is expressed in most tissues under physiologic conditions, whereas COX-2 is induced by mediators of inflammation under pathologic conditions (Fig. 3). Investigators have studied the relative inhibitory effects of NSAIDs on COX-1 and COX-2 activities. It appears that the risk of certain side effects correlates with the ability of NSAIDs to inhibit COX-1, whereas the anti-inflammatory effects are a result of their ability to inhibit COX-2. Clinical trials and clinical experience to date have confirmed the efficacy and favorable side-effect profile of these drugs, particularly with regard to their effect on the gastric mucosa.

Figure 3. Relationships between the pathways leading to the generation of prostaglandins, thromboxanes, and other eicosanoids by COX-1 or COX-2.

II. ADVERSE EFFECTS AND CONTRAINDICATIONS
Unfortunately, the NSAIDs are not free of bothersome, and sometimes even dangerous, adverse effects (Table 3). Many patients cannot tolerate these drugs because of their gastrointestinal (GI) effects. Several hundred deaths per year are the result of GI bleeding induced by chronic NSAID use, the elderly being particularly susceptible. After the introduction of the injectable nonsteroidal ketorolac, the drug became very popular for postoperative pain. There followed a rash of reported problems with the drug, the most serious of these being catastrophic GI bleeding. It is unclear, as yet, whether these problems were the result of the inappropriately high dose initially recommended by the manufacturers (now reduced by 50%) or the sudden widespread use of a potent NSAID in the vulnerable postoperative patient population.

Table 3. Principal adverse effects of long-term NSAID therapy

Yet these events do suggest caution in the use of NSAIDs in postoperative patients, particularly after major surgery. As GI complications are the most troublesome adverse effects, the introduction of a new class of NSAIDs, the selective COX-2 inhibitors, which have been shown to be associated with significantly fewer GI complications, is an exciting advance.
1. Gastrointestinal effects
Prostaglandins inhibit acid secretion by blocking the activation of parietal cells by histamine. At the same time, they are cytoprotective in that they stimulate mucus production from the upper GI tract. By inhibiting prostaglandins, NSAIDs cause gastroduodenal mucosal lesions and ulcers. Gastritis, resulting in abdominal pain, nausea, and vomiting and sometimes diarrhea, is an extremely common side effect of NSAIDs that occurs particularly in persons with a propensity to peptic ulceration; it occasionally results in catastrophic GI bleeding and death. It is accepted practice to withhold NSAIDs from patients with known peptic ulcer disease.
The risk of GI toxicity can be scored using the ARAMIS (American Rheumatism Association Medical Information System) scoring system (Table 4). This system provides a guide for assessing patients’ suitability for NSAID treatment, or their suitability for concomitant prophylactic treatment. Prostaglandin analogs such as misoprostol , parietal cell inhibitors (acid inhibitors) such as omeprazole , and histamine antagonists such as ranitidine and cimetidine can provide useful prophylaxis against NSAID-induced GI symptoms. The selective COX-2 inhibitors, being associated with less GI toxicity than standard NSAIDs, are a good choice for patients with a history of GI symptoms or sensitivity to NSAIDs. However, they are expensive ($4.80 per day for celecoxib, $2.20 per day for rofecoxib , versus $0.24 per day for generic ibuprofen), and many payers require that physicians prescribe the much cheaper combination of a standard NSAID with prophylaxis, which is thought to be equally effective in terms of efficacy and freedom from GI toxicity.

Table 4. The ARAMIS model for estimating the risk of gastric ulceration while taking nonselective NSAIDs

2. Decreased hemostasis
The decreased hemostasis associated with NSAIDs is largely the result of platelet dysfunction. Cyclooxygenase inhibition also inhibits the endogenous procoagulant thromboxane. Platelets are especially susceptible to cyclooxygenase inhibition because they have little or no capacity for protein biosynthesis and thus cannot regenerate the enzyme. The literature confirms that bleeding time is consistently prolonged in patients receiving long-term NSAID treatment, but the consensus is that such prolongation is not excessive, and that values remain below the upper limits of normal. However, NSAIDs are usually withheld from patients with a coagulopathy and from patients on anticoagulant therapy. Before surgery, NSAIDs are usually stopped for at least 24 hours, or 10 to 14 days in the case of aspirin, whose platelet effects are not as rapidly reversed as those of other NSAIDs because of irreversible covalent binding to COX. It is still unclear whether the selective COX-2 inhibitors damage platelet function to the same extent, but early studies suggest that they do not.
3. Surgical bleeding
The degree of risk of perioperative bleeding in patients treated with NSAIDs is not very clear. Some studies show increased blood loss in patients treated with NSAIDs, whereas others fail to show this effect. Increased bleeding in NSAID-treated patients undergoing major abdominal surgery, hysterectomy, and tonsillectomy has been reported. Several reports of perioperative bleeding associated with the use of ketorolac have recently appeared. Most commonly, this is GI bleeding, but there are also reports of hematoma formation and hemarthrosis after knee surgery. As mentioned earlier, it is as yet unclear whether the high reported incidence of GI hemorrhage associated with ketorolac is a function of the excessively high doses used before the manufacturers recommended a lower dose or whether this problem will still occur after decreasing the dose.
4. Renal dysfunction and failure
Prostaglandins in the kidney contribute to the maintenance of renal blood flow and glomerular filtration, to the modulation of renin release and tubular ion transport, and to the excretion of water. In normal, sodium-repleted, well-hydrated individuals, the role of prostaglandins in the kidney is less important than it is in patients with abnormal renal function, hypovolemia, or abnormal serum electrolytes, in whom local synthesis of vasodilating prostaglandins is important in maintaining renal homeostasis. In these patients, NSAID administration may decrease the glomerular filtration rate and result in the release of renin from the juxtaglomerular cells, leading to further reduction in renal blood flow and a disturbance of renal function. The most common clinical picture is of a small and rapidly reversible fall in the glomerular filtration rate, which occasionally progresses to acute renal failure. Sodium and water retention, hyperkalemia, hypertension, papillary necrosis, and the nephrotic syndrome are other possible consequences of the renal disturbance.
Although NSAID-induced renal dysfunction is extremely rare in healthy patients, it is a significant risk for patients with renal compromise, this risk increasing with prolonged and excessive NSAID use. The elderly, and patients with chronic renal dysfunction, congestive heart failure, ascites, or hypovolemia, and patients treated with nephrotoxic drugs such as the aminoglycosides and vancomycin, are at particular risk. Early clinical studies suggest that the selective COX-2 inhibitors have renal effects similar to those of nonselective NSAIDs. Thus, this new class of drugs does not appear to spare the kidneys.
Recent opinion, in contrast to the traditional view, suggests that renal effects can occur after only a few days (not weeks) of NSAID treatment. Does this mean that patients undergoing major surgery, who are liable to become hypovolemic during the perioperative period, have an increased risk of renal toxicity from NSAIDs, even with short-term use? Our experience to date with ketorolac is that it appears to be safe to the kidneys in healthy patients, without preoperative renal risk factors, undergoing minimally invasive surgery not associated with significant fluid shifts or major blood loss. It is a sensible precaution, however, to reserve NSAIDs for the postoperative period in patients undergoing major surgery, thus avoiding preoperative or intraoperative administration in those who face the possibility of blood loss, hypotension, and hypovolemia.
5. Drug interactions
NSAIDs are highly bound to albumin in plasma, and adverse drug interactions could potentially occur because of this high degree of binding. However, NSAIDs do not seem to alter the effects of the oral hypoglycemic drugs or warfarin. Warfarin doses may need to be altered because of the platelet effects of NSAIDs, and concomitant use may be contraindicated. Reduced doses of NSAIDs are recommended in severely hypoalbuminemic patients. NSAIDs may also reduce the diuretic and natriuretic effects of furosemide, as well as the antihypertensive effects of the thiazide diuretics, b-adrenergic antagonists, and angiotensin-converting enzyme inhibitors, probably because of inhibition of renal or vascular prostaglandin synthesis.
6. Other adverse effects
Other adverse effects are less common. The incidence of immunerelated hypersensitivity is low, the most serious effect being dosedependent, potentially fatal hepatic necrosis. Asthma can occur in susceptive individuals, not due to hypersensitivity but rather to blockade of the cyclooxygenase pathway leading to exaggerated leukotriene effects. Some patients display intolerance to NSAIDs in the form of vasomotor rhinitis, angioneurotic edema, generalized urticaria, asthma, laryngeal edema, hypotension, and even shock. Despite the resemblance to anaphylaxis, these reactions do not appear to be immunologically based.
Prolonged or excessive use of acetaminophen (>10g/day) can cause potentially fatal centrilobular hepatic necrosis. For this reason, acetaminophen (alone or in combination preparations such as Percocet), should not be used for prolonged, chronic pain therapy. NSAIDs are known to impede cartilage repair, which has become a problem for some patients who have osteoarthritis and take NSAIDs for long periods of time (i.e., years).
NSAIDs adversely affect osteogenesis in animals. Although impaired bone remodeling and delayed fracture healing have not been firmly established in humans, many surgeons prefer to avoid the use of NSAIDs in patients who have undergone bone fusion, particularly in the spine. NSAIDs have been associated with decreased healing of GI anastomoses, but this association is rare and not confirmed in humans.
By way of summary, contraindications are listed in Table 5.

Table 5. Contraindications to NSAID use

III. NEW NSAIDs
Over the last few decades, NSAIDs have proved themselves to be highly effective, popular, and useful analgesics, but they are plagued by their side effects. It is not surprising, therefore, that pharmaceutical companies are committing huge resources to the search for NSAID formulations with more favorable side-effect profiles. Several approaches are taken.
1. Differential inhibition of cyclooxygenase isoenzymes
The most advanced development is that of cyclooxygenase isoenzyme-specific inhibitors. The first of this group of drugs (celecoxib) became available in the United States in 1999, and rofecoxib is now also available. These two drugs and meloxicam have been used in Europe for several years.
In large clinical trials, COX-2 inhibitors have been shown to be at least as effective as existing NSAIDs, with a significantly improved side-effect profile. The improved safety is largely the result of a marked decrease in the incidence and severity of GI complications. COX-2 seems to play an important role in human renal function, and as a group, the selective COX-2 inhibitors do not appear to spare the kidneys when compared with standard NSAIDs. However, there are some differences that may favor the selective COX-2 inhibitors, and studies to date have not fully elucidated the renal effects of these newer NSAIDs. Platelet function does seem to be preserved.
Another notable benefit of these drugs is that they appear to have no effect on cartilaginous repair. They have also been shown to inhibit colorectal tumor cell growth, and early trials indicate that they may prove to be a useful treatment for delaying premature labor.
2. New stereoisomers
Pure enantiomers of 2-propionic acid derivatives have recently been isolated, allowing study of their individual properties. It is already clear that the R- and S-enantiomers act differently, both in the periphery and in the central nervous system, and that it may be possible to develop clinically useful analgesics, free from significant peripheral prostaglandin inhibition and thus free from GI and renal toxicity.
3. Central nervous system activity
Although acid NSAIDs do not readily cross the blood–brain barrier, and a large proportion of the NSAID effect is in the periphery, a central contribution to NSAID effects appears established. Several mechanisms for this effect have been proposed, including prostaglandin inhibition in neural tissue, inhibition of nitric oxide systems via inhibition of N-methyl-D-aspartate (NMDA) and substance P systems, interaction with G proteins, modulation of neurotransmitter release, and amelioration of glutamate receptor–directed gene expression. This is an exciting area that could lead to the development of NSAIDs with a more useful central nervous system effect, for administration either neuraxially or systemically.
4. Other approaches
Other strategies under study include coupling NSAIDs to nitric oxide–releasing compounds, preassociation of NSAIDs with zwitterionic phospholipids to prevent NSAID–mucosal interactions, and concomitant administration of trefoil peptides to stimulate mucosal defense pathways. The clinical feasibility of these strategies remains to be determined.
IV. NSAID USE IN SPECIFIC POPULATIONS
Physicians commonly prescribe NSAIDs for acute and chronic pain, particularly for pain resulting from surgery and trauma and pain caused by joint disease. Commonly used NSAIDs and their dosages are presented in Appendix VIII. They are also available over the counter and are widely used as household analgesics. Thus, not only are physicians responsible for appropriate prescribing of NSAIDs, they also need to advise patients about the safe and appropriate use of over-the-counter preparations. These factors are will be discussed further.
1. Perioperative patients
(i) Domestic use—cautions
NSAIDs are the most ubiquitous of drugs. Most are available without prescription. They are widely used for minor aches and pains, for headaches, for menstrual cramps, and for the chronic arthritides. Patients should be advised to stop taking NSAIDs before surgery, chiefly because of their platelet effects and their propensity to increase surgical bleeding. Aspirin, whose platelet effects are not reversible, should be stopped for 10 to 14 days before elective surgery. Other NSAIDs have rapidly reversible platelet effects, and 24 hours cessation is probably sufficient, although a 2- to 3-day cessation is usually advised. Acetaminophen, which has only mild peripheral effects and does not affect platelets, can be substituted. Spinal and epidural instrumentation and catheter placement appear to be safe even if aspirin and other NSAIDs are not discontinued.
(ii) Postoperative and acute pain
NSAIDs are extremely useful, and often underutilized, for acute and postoperative pain. Broadly, there are two indications in this population: (a) as a sole analgesic for mild pain, and (b) as an adjunct to other analgesics in severe pain.
a) Mild Pain
The efficacy of NSAIDs for mild acute pain is well established by countless randomized controlled trials. However, until recently, their widespread applicability for postoperative pain was limited because of the lack of availability of parenteral formulations and the limitations this placed on the use of NSAIDs in patients who cannot take oral medications. Prompted by the availability of rectal and parenteral preparations, the value of NSAID treatment in postoperative patients has now been realized, and both enteral and parenteral preparations are being used preoperatively, intraoperatively, and postoperatively, providing useful postoperative analgesia.
The use of NSAIDs allows for complete avoidance, or minimal use, of opioids during and after minor surgery, thus avoiding the opioid-induced side effects (nausea and somnolence) that commonly delay recovery and discharge. NSAID side effects are rare in the relatively healthy day surgery population, and with short-term use. NSAIDs (unless contraindicated) are arguably the treatment of choice for pain after minor surgery, and late in the postoperative course after major surgery.
Acetaminophen is a popular choice, particularly in infants, as it avoids GI irritation. Combinations of opioid and acetaminophen are also widely prescribed for mild to moderate acute and postoperative pain.
b) Adjunct use and opioid sparing
For more severe acute pain, NSAIDs alone may be ineffective, but in conjunction with other modes of pain treatment they have an important role. Opioids will probably always hold a place in the management of acute somatic pain because they are highly effective, and they are the only analgesics that have no ceiling effect. However, their side effects, particularly respiratory depression, severely limit their use. There are many ways to reduce opioid requirement, including the use of local nerve blocks, the use of epidural and intrathecal anesthesia and analgesia, and the use of nonopioid analgesics, including NSAIDs. A multimodal approach, using a combination of appropriate pain treatments, appears to be the best way to achieve synergy between different modes of treatment and to reduce the side effects of each.
Multiple controlled trials confirm the opioid-sparing effects of NSAID usage in postoperative pain. Whether this reduction in opioid consumption can be translated into a significant difference in the incidence of opioid-associated side effects or in improved overall outcome is less clear. Certainly there are groups of patients in whom opioid treatment and opioid side effects are particularly undesirable, including the very young, those with preexisting ventilatory compromise, and those with a strong history of opioid-induced side effects. These patients are not widely studied in trials, yet they are the patients for whom NSAIDs may be particularly advantageous.
The adjunctive use of NSAIDs is also useful in patients receiving epidural treatment for postoperative pain. Trials of NSAIDs for this indication have yet to appear in the literature in great numbers, but in practice, the addition of an NSAID to epidural opioid therapy often makes the difference between adequate and inadequate pain control.
c) Adverse effects
The adverse effects of NSAIDs in surgical patients are summarized in Table 6.

Table 6. Adverse effects of NSAIDs in surgical patients

d) Timing of administration
There is no consensus regarding timing of NSAID doses in patients undergoing surgery, even though speed of onset influences the usefulness of the drugs. In studies that specifically examine the issue of timing of doses and effects, the benefit of NSAIDs was not seen until 4 hours or more after the parenteral administration of an NSAID (ketorolac or other), and effectiveness continued to improve even after administration. Is it advisable, then, to start NSAID treatment preoperatively?
Pretreatment demonstrated superior efficacy when it was assessed in dental patients. However, in a large meta-analysis of the general surgical population, no measurable difference was found between the same dose given preoperatively and given postoperatively. Moreover, as discussed, NSAID pretreatment may be ill advised before major surgery because of the risks of hypovolemia, hypotension, bleeding, and renal compromise. The question of when to treat is a complex one that needs to be addressed by research into the clinical benefit versus cost benefit of pretreatment with NSAIDs. Currently, it is probably better to offer preoperative oral NSAIDs to patients undergoing minor surgery, and to reserve injectable NSAIDs for the end of surgery or for postoperative use.
e) Ketorolac
Ketorolac was introduced in the United States in 1990, and it was the first NSAID to have approval from the U.S. Food and Drug Administration for parenteral use in postoperative patients. Ketorolac differs from other NSAIDs in two respects: not only is it injectable, it is also highly efficacious, with efficacy close to that of morphine. For these reasons, it has been widely adopted for use in acute and postoperative pain.
Unfortunately, ketorolac also has side effects, and there are many reported cases of problems associated with its use, possibly caused by inappropriately high doses or by failure to recognize contraindications. The most common and serious side effects have been GI bleeding, other bleeding problems, and reversible renal dysfunction.
Ketorolac has been found to be as effective as morphine and other opioids for surgery ranging from simple outpatient procedures to major operations. At the same time, investigators have demonstrated the efficacy of other NSAIDs, traditionally considered weak analgesics, to be equal to that of ketorolac for mild pain. Were it not that ketorolac is markedly more expensive than other NSAIDs ($6.50 versus a few cents per dose) and suitable only for short-term use, the efficacy of ketorolac might dictate that it be the NSAID of choice for postoperative pain in most situations. However, cost and side effects limit it’s usefulness. Whenever oral dosing is possible, other NSAIDs, not ketorolac, should be considered the first-line NSAID treatment for mild to moderate pain. For more severe pain, other NSAIDs may be inadequate and unhelpful, and then ketorolac contributes significantly to the attenuation of pain.
2. Chronic noncancer pain patients
By far the most common indication for NSAIDs, and the biggest market for drug companies, is joint pain. Other indications for NSAID use in patients with chronic noncancer pain are myalgias, headache, and mild to moderate pain of any etiology.
(i) Joint pain
The NSAIDs are the first-line pharmacologic treatment for in-flammatory joint diseases, including osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and scleroderma. They are used to treat both pain and inflammation in these diseases. So effective are they at improving the quality of life for these patients that the significant risk of GI toxicity is accepted, despite the occurrence of several deaths per year from catastrophic GI bleeding in this population. As discussed, the race is on to develop effective antiinflammatory analgesics that are free from GI toxicity. The new selective COX-2 inhibitors hold the greatest hope for these patients at present, and they are rapidly gaining popularity. The treatment of large-joint pain is largely the province of rheumatologists and primary physicians, and these patients rarely present to pain clinics unless they have intractable back or neck pain.
(ii) Other indications
NSAIDs are useful therapy for myalgias, including fibromyalgia, and for other muscle pains that may occur in conjunction with joint pain, particularly back pain. In noncancer patients, perhaps the most common indication for NSAIDs in pain clinics is headache. Acetaminophen and NSAIDs are useful first-line treatments for both migraine and tension headaches. If nausea is a prominent feature of a patient’s headaches, an antiemetic can be added, or the gastric route can be avoided by using a rectal or parenteral preparation. Intramuscular ketorolac is useful in some patients. Even if therapy with an NSAID alone is not sufficient for headaches, its combination with other treatments such as vasoconstrictors (caffeine, ergotamine, sumatriptan) is often useful. In addition, NSAIDs can be tried as a first line treatment for any mild to moderate pain.
The choice of NSAID for any indication is largely a matter of trial and error. The older, cheaper NSAIDs (aspirin, indomethacin , and phenylbutazone) are often poorly tolerated because of their GI effects. They also need frequent doses. Aspirin is the oldest and cheapest of the NSAIDs, and it maintains its place as a useful analgesic despite its side-effect profile. Several formulations (e.g., buffered and enteric coated) are available that are less toxic to the GI tract. Ibuprofen, the most popular of the newer NSAIDs, is less toxic than the older drugs but still needs 4- to 6-hour dosing to maintain therapeutic levels. Naproxen and diflunisal are widely used for chronic pain because they are long acting and need only twice-daily dosing. Nabumetone (a nonacidic prodrug metabolized to a structural analog of naproxen) is minimally toxic to the GI tract and has been the treatment of choice when GI side effects are a problem. The COX-2 inhibitors (celecoxib and rofecoxib) are also minimally toxic to the GI tract. The COX-2 inhibitors may become the NSAIDs of choice if they hold to their promise of being effective and having a superior side-effect profile. Despite these logical considerations, it is often necessary to try out different NSAIDs before finding the best drug for an individual patient.
3. Cancer patients
In cancer pain patients, acetaminophen and NSAIDs are used as a first-line therapy for mild to moderate pain, in combination with opioids for more severe pain, and especially for bone and inflammatory pain in advanced cancer.
(i) The World Health Organization guidelines
In 1986, the World Health Organization (WHO) released a set of guidelines called Cancer Pain Relief. The central component is the “three-step analgesic ladder” (see Chapter 32, figure 1), which became the guiding principal for cancer pain treatment in many parts of the world. The three-step analgesic ladder recommends initial treatment with nonopioid analgesics, alone or with adjuvants (e.g., anticonvulsants, antidepressants); advancing to mild opioids, alone or in combination with nonopioid analgesics and adjuvants; and finally to potent opioids, alone or in combination. Although new drugs and techniques have in some measure altered the way we might wish to treat cancer pain, the basic principles in the WHO guideline are still sound for cancer pain treatment.
Since the advent of more potent NSAIDs, the question arises whether the second step in the ladder (the use of opioid with or without nonopioid analgesic, with or without adjuvant) should be abandoned in favor of simply continuing the first step (the use of nonopioid analgesics with or without adjuvant) for mild to moderate pain. However, there is still a safety issue, and at present, opioid plus nonopioid combinations maintain their place for mild to moderate cancer pain, because these combinations exhibit synergy and have the ability to reduce the side effects of each drug. The advent of an even more potent and safer NSAID may well change the way we treat moderately severe, or even severe, cancer pain.
(ii) The role of NSAIDs in advanced cancer
In advanced cancer, NSAIDs are particularly useful for bone pain (caused by distention of the periosteum by metastases), for soft tissue pain (caused by compression or distention of tissues), and for visceral pain (caused by irritation of the pleura or peritoneum). Of particular concern in these patients is the platelet effect of NSAIDs and the risk of inducing bleeding. Many of these patients suffer general debilitation, with resultant effects on protein synthesis, including the synthesis of clotting factors. They commonly have thrombocytopenia or pancytopenia as a result of the underlying malignancy or prior therapy.
The nonacetylated salicylates (salsalate , sodium salicylate , choline magnesium trisalicylate) are often substituted for other NSAIDs in patients at risk, because they do not profoundly affect platelet aggregation and do not alter bleeding time. Whether the selective COX-2 inhibitors will prove to be safe in cancer patients with a bleeding risk is as yet unclear.
V. CONCLUSION
NSAIDs are useful analgesics with a predominantly peripheral action that can provide sole treatment for mild pain, or that can complement the central effects of opioids and neuraxial analgesics for more severe pain. Were it not for their side effects, which are occasionally catastrophic, NSAIDs would be more widely used. Several developments in NSAID pharmacology are leading toward the introduction of more efficacious and safer drugs that will undoubtedly influence pain treatment for both acute and chronic pain.
SELECTED READING

1.
Kenny GNC. Potential renal, haematological and allergic adverse effects associated with nonsteroidal anti-inflammatory drugs. Drugs 1992;44(suppl 5):31–37.

2.
Laneuville O, Breuer DK, Dewitt DL, et al. Differential inhibition of human prostaglandin endoperoxide H synthases-1 and -2 by nonsteroidal anti-inflammatory drugs. J Pharmacol Exp Ther 1994; 271:927–934.

3.
Mather LE. Do the pharmacodynamics of the nonsteroidal anti-inflammatory drugs suggest a role in the management of postoperative pain? Drugs 1992;44(suppl 5):1–13.

4.
McCormack K. The spinal actions of NSAIDs and the dissociation between anti-inflammatory and analgesic effects. Drugs 1994;47: 28–45.

5.
Moote C. Efficacy of nonsteroidal anti-inflammatory drugs in the management of postoperative pain. Drugs 1992;44(suppl 5):14–30.

6.
Souter AJ, Fredman B, White PF. Controversies in the perioperative use of nonsteroidal antiinflammatory drugs. Anesth Analg 1994; 79:1178–1190.

7.
Vane JR, Botting RM. Mechanism of action of aspirin-like drugs. Semin Arthritis Rheum 1997;26(suppl 1):2–10.

8.
Wolfe MM. Future trends in the development of safer nonsteroidal anti-inflammatory drugs. Am J Med 1998;105:44S–52S.

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3 comments on “8 Nonsteroidal Anti-inflammatory Drugs

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