**5. Nonsteroidal anti‐inflammatories**

Similar to paracetamol, NSAIDs exert their analgesic, antipyretic and anti‐inflammatory effects through the inhibition of COX isoenzymes [18, 20]. NSAIDs specifically target COX‐1 and COX‐2, and enzyme affinity varies among agents. It is this isoenzyme selectivity that determines the efficacy and safety profile of these agents. As a group, NSAIDs typically are used as second‐line agents in the treatment of acute and chronic low back pains after paracetamol [1, 7]. NSAIDs are more potent analgesics when compared to paracetamol for the treatment acute pain, but they are also associated with gastrointestinal, renal and cardiovas‐ cular complications with chronic use [14, 21]. At high doses, NSAIDs can even have compa‐ rable analgesic effects to low‐dose opioids without the respiratory depressant effects. When evaluating the clinical efficacy among NSAIDs, no study has shown that one agent is better than another [20]. Therefore, when selecting an agent, careful consideration of each agent's safety and pharmacokinetic profile should be considered.

There are several different classes of NSAIDs, and most classes have multiple agents as well. For the purposes of this chapter, we will be focusing on those agents commonly used to treat acute and chronic pains. In order to treat low back pain effectively, an NSAIDs must be avail‐ able orally and have good bioavailability, a fast onset of action, convenient dosing interval and minimal drug‐drug interactions (**Table 1**). Of note, several NSAIDs (diclofenac, ibupro‐ fen and ketoprofen) have topical formulations that likely provide similar analgesic effects as their oral counter parts, but are associated with less systemic side effects [22]. Additionally, other dosage forms may be available to treat acute pain in patients unable to take oral medi‐ cations. For example, there are intravenous formulations of ketorolac and ibuprofen that can be used in the hospitalized setting to treat acute pain. Similarly, rectal formulations are also available for several NSAIDs, but their long‐term use for analgesia is inconvenient and com‐ parative efficacy is unknown.


[11, 14]. Chronic alcoholism is especially worrisome for patients taking high doses of paracetamol on a daily basis. Chronic alcohol intake causes hepatotoxicity through a completely indepen‐ dent pathway as well as increasing CYP450 activity and depleting glutathione stores. Both of these increase the production of NAPQI. Therefore, in alcoholics, total daily doses should be

Other less common, but notable side effects of paracetamol therapy include hypersensitiv‐ ity reactions and elevations in international normalized ration (INR) [11, 18, 19]. When patients were given 4 g of paracetamol a day for 14 days, there was a mild increase in INR as well as a mild decrease in vitamin K‐dependent clotting factors. This supports closer monitoring when patients are being co‐administered warfarin and paracetamol for long periods of time. Intravenous doses of 1 g have been shown to cause very minor decreases in platelet aggregation, but overall paracetamol should be considered safe to use in the setting of an elevated bleeding risk. It is because of the lack of side effects and relative tolerability of paracetamol that it is recommended as the first‐line agent in treating acute

Similar to paracetamol, NSAIDs exert their analgesic, antipyretic and anti‐inflammatory effects through the inhibition of COX isoenzymes [18, 20]. NSAIDs specifically target COX‐1 and COX‐2, and enzyme affinity varies among agents. It is this isoenzyme selectivity that determines the efficacy and safety profile of these agents. As a group, NSAIDs typically are used as second‐line agents in the treatment of acute and chronic low back pains after paracetamol [1, 7]. NSAIDs are more potent analgesics when compared to paracetamol for the treatment acute pain, but they are also associated with gastrointestinal, renal and cardiovas‐ cular complications with chronic use [14, 21]. At high doses, NSAIDs can even have compa‐ rable analgesic effects to low‐dose opioids without the respiratory depressant effects. When evaluating the clinical efficacy among NSAIDs, no study has shown that one agent is better than another [20]. Therefore, when selecting an agent, careful consideration of each agent's

There are several different classes of NSAIDs, and most classes have multiple agents as well. For the purposes of this chapter, we will be focusing on those agents commonly used to treat acute and chronic pains. In order to treat low back pain effectively, an NSAIDs must be avail‐ able orally and have good bioavailability, a fast onset of action, convenient dosing interval and minimal drug‐drug interactions (**Table 1**). Of note, several NSAIDs (diclofenac, ibupro‐ fen and ketoprofen) have topical formulations that likely provide similar analgesic effects as their oral counter parts, but are associated with less systemic side effects [22]. Additionally, other dosage forms may be available to treat acute pain in patients unable to take oral medi‐ cations. For example, there are intravenous formulations of ketorolac and ibuprofen that can be used in the hospitalized setting to treat acute pain. Similarly, rectal formulations are also available for several NSAIDs, but their long‐term use for analgesia is inconvenient and com‐

limited to 2 g [18].

188 Pain Relief - From Analgesics to Alternative Therapies

and chronic pains.

**5. Nonsteroidal anti‐inflammatories**

safety and pharmacokinetic profile should be considered.

parative efficacy is unknown.


**Table 1.** Properties of common NSAIDs (ordered in increasing COX‐2 selectivity).

The most common adverse reactions with chronic NSAID use are those associated with the upper GI tract [13, 19, 20]. These adverse reactions are dose dependent in nature, and patients are placed at increasing risk as doses are escalated for increased analgesia activity. For exam‐ ple, when ibuprofen is used at doses of 800–1200 mg a day, risk for GI bleed was not signifi‐ cantly different than placebo [13]. Additionally, as doses are escalated, the odds of a GI bleed nearly double when doses of ≤600 mg/day were compared to doses of >1200 mg/day [19]. Adverse reactions are uncommon with chronic NSAID use, with up to 20% of patients report‐ ing dyspepsia during treatment [18, 20]. Other common adverse reactions include anorexia, nausea, abdominal pain and diarrhea.

GI adverse reactions are mediated through two possible mechanisms [18, 20]. Through inhibi‐ tion of COX‐1, NSAIDs decrease cytoprotective prostaglandin production in the gastric epi‐ thelial cells. This causes an increase in acid secretion, a decrease in mucosal blood flow and a decrease in the production of the protective mucous layer. The second proposed mecha‐ nism is through local irritation to mucosal cells. NSAIDs are week acids, and in the acidic environment of the stomach, they stay unionized and readily diffuse into mucosal epithelial cells. Once inside cells, these acids trap hydrogen ions and cause cell damage. Risk factors for NSAID‐induced GI injury include age > 65 years, tobacco use, alcohol consumption, con‐ current use of steroids, anticoagulation, prior history of GI ulceration and increasing dose or duration of NSAIDs. Of note, formulations whose goal is to decrease direct contact with gas‐ tric mucosa (e.g., enteric coating) have not shown to reduce the incidence of major GI adverse reactions. However, it is recommended to utilize acid suppression therapy (histamine blockers or proton pump inhibitors) in patients on chronic high doses of NSAIDs to aid in the preven‐ tion of gastric and duodenal ulcers [18, 19].

Due to these common side effects, a subset of NSAIDs was developed to selectively inhibit only the COX‐2 isoenzyme. There are much lower concentrations of COX‐2 in the upper GI tract, and by sparing inhibition to COX‐1, the detrimental effects seen with nonselective NSAIDs on the GI mucosa are greatly diminished [19, 20]. Fortunately, this selective inhibition of COX‐2 does not seem to decrease the analgesic effects of COX‐2 selective NSAIDs when compared to nonselective NSAIDs [23]. However, because there are higher concentrations of COX‐2 in cardiovascular (CV) tissue, COX‐2 selective NSAIDs have been associated with increased CV risk. This has led to the majority of COX‐2 selective agents to being pulled from the market [13]. With this consideration in mind, COX‐2 selective NSAIDs may be advantages in patients with history of GI ulcers, dyspepsia, gastroesophageal reflux disease or other similar disor‐ ders and are otherwise good candidates for treatment with NSAIDs [20]. Similar to nonselec‐ tive NSAIDs, use in the setting of acute pain is reasonable, but careful consideration must be made when used chronically as long‐term risk likely outweighs benefit.

Another adverse effect of NSAIDs that goes hand in hand with the increased risk for GI adverse reactions is the risk of platelet inhibition. Through inhibition of the COX‐1 isoenzyme, NSAIDs attenuate the production of thromboxane A2 [19]. By decreasing the production of thromboxane A2, NSAIDs reversibly inhibit platelet aggregation and clot formation and if combined with other drugs that carry a bleeding risk the effect is additive. One case‐control study that looked at NSAID use combined with selective serotonin reuptake inhibitors found that the incidence of upper GI bleed or ulcer was three when the agents were used alone [24].

The most common adverse reactions with chronic NSAID use are those associated with the upper GI tract [13, 19, 20]. These adverse reactions are dose dependent in nature, and patients are placed at increasing risk as doses are escalated for increased analgesia activity. For exam‐ ple, when ibuprofen is used at doses of 800–1200 mg a day, risk for GI bleed was not signifi‐ cantly different than placebo [13]. Additionally, as doses are escalated, the odds of a GI bleed nearly double when doses of ≤600 mg/day were compared to doses of >1200 mg/day [19]. Adverse reactions are uncommon with chronic NSAID use, with up to 20% of patients report‐ ing dyspepsia during treatment [18, 20]. Other common adverse reactions include anorexia,

**Drug name Dosage forms Typical dose (mg) Dosing interval (h) COX selectivity Comments**

Celecoxib Oral 100–200 12 COX‐2 Dose reduction

Immediate release: 6–8; Extended release: 24

Immediate release: 6–8; Extended release: 24

COX‐2 Edema is a

COX‐2 Similar COX‐2

selectivity as celecoxib

common side effect (33% of patients)

is necessary in CYP2C9 poor metabolizers (\*3/\*3 allele) although not commonly known; May carry higher cardiovascular risk than other nonselective NSAIDs

Immediate release: 25–50; Extended release: 50–75

Immediate release: 200–400; Extended release: 400–1000

**Table 1.** Properties of common NSAIDs (ordered in increasing COX‐2 selectivity).

GI adverse reactions are mediated through two possible mechanisms [18, 20]. Through inhibi‐ tion of COX‐1, NSAIDs decrease cytoprotective prostaglandin production in the gastric epi‐ thelial cells. This causes an increase in acid secretion, a decrease in mucosal blood flow and a decrease in the production of the protective mucous layer. The second proposed mecha‐ nism is through local irritation to mucosal cells. NSAIDs are week acids, and in the acidic environment of the stomach, they stay unionized and readily diffuse into mucosal epithelial cells. Once inside cells, these acids trap hydrogen ions and cause cell damage. Risk factors for NSAID‐induced GI injury include age > 65 years, tobacco use, alcohol consumption, con‐ current use of steroids, anticoagulation, prior history of GI ulceration and increasing dose or duration of NSAIDs. Of note, formulations whose goal is to decrease direct contact with gas‐ tric mucosa (e.g., enteric coating) have not shown to reduce the incidence of major GI adverse reactions. However, it is recommended to utilize acid suppression therapy (histamine blockers

nausea, abdominal pain and diarrhea.

Diclofenac Oral (immediate release, extended release); Suppository; Gel

190 Pain Relief - From Analgesics to Alternative Therapies

Etodolac Oral (immediate release, extended release)

> Other limiting factors shown with chronic therapy include an increased cardiovascular throm‐ botic risk, blood pressure and renal toxicity. While each of these adverse events occurs sepa‐ rately, they are intertwined through pathophysiology. CV risk is likely caused by decreased production of COX‐2‐dependent prostaglandins in the kidney. These prostaglandins nor‐ mally blunt the effect that prothrombotic and atherogenic inputs have on the coronary vas‐ culature [25]. Without this protection, the risk for CV‐related events elevates. Blood pressure and renal toxicity are affected in a somewhat similar matter. In patients who have increased activation of the renin‐angiotensin and elevated blood pressure, NSAIDs disrupt the tenuous balance that renal prostaglandins play a key role in maintaining homeostasis. When COX‐2 is inhibited and these prostaglandins are reduced, antidiuretic hormone is blunted and chlo‐ ride ions are reabsorbed to a greater degree. This causes sodium and water retention and an elevation in blood pressure [18]. A similar process is commonly described to explain the NSAID‐induced renal injury. The same prostaglandins that regulate chloride reabsorption also maintain renal blood flow. Homeostasis normally occurs through reducing the effects of adrenergic or renin‐angiotensin inputs. When removed, arterial constriction occurs, blood supply decreases and renal toxicity occurs [26].

> Even with a large number of potential side effects, NSAIDs are a great option to treat low back pain, especially if it is only for a short duration. Caution should be advised when consider‐ ing treating for longer durations and when a patient has co‐morbid disease states or is at risk for adverse reactions. If it is used chronically, make sure the lowest efficacious dose is being

used. Additionally, if a clinician commonly prescribes NSAIDs, they should be diligent in following new evidence on efficacy and safety of individual agents to assist them in select‐ ing the most ideal one. When considering a patient's analgesic regimen, NSAIDs are a viable first‐ or second‐line treatment choice if the risks for drug‐related complications are low [1, 6]. In relation to the WHO's stepwise ladder, adding a NSAID is especially useful if a patient has an acute increase in pain (acute injury, worsening breakthrough pain, etc.) and even more so if the acute pain process has an inflammatory component. Ideally, when the acute pain event is resolved or mitigated, the clinician can shift back down the pain ladder and remove the NSAID from the regimen.
