Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in The Treatment of Acute Low Back Pain

Pain/Inflammation Reduction
The primary mechanism of action in NSAIDs is a reduction of cyclooxygenase (enzymes that make prostaglandins) activity and a resultant decrease in prostaglandin synthesis. Prostaglandins are active mediators of the inflammatory cascade, which also serve to sensitize peripheral nociceptors (nerve endings). A reduction in their local concentration could therefore explain the combined anti-inflammatory and analgesic properties of NSAIDs.

In single doses, most of the NSAIDs are more effective analgesics than a single dose of acetaminophen or aspirin. Locally, NSAIDs are also felt to combat inflammation by inhibiting neutrophil (destroys cellular debris) function and interfering with the activity of enzymes such as phospholipase C (an enzyme). Most NSAIDs do not decrease the production of lipoxygenase-produced leukotrienes (causes inflammation and allergic reactions), which are also believed to significantly contribute to the inflammatory response.

A disparity between the anti-inflammatory and analgesic potencies of these agents in clinical practice has been observed, and recent data has suggested that pain relief from NSAIDs may in part be secondary to a more central anti-nociceptive component. Measurable levels of anti-inflammatory agents are appreciated in the cerebrospinal fluid (CSF) following short-term administration in the setting of a soft tissue injury.

Types of NSAIDs
NSAIDs include aspirin, which inhibits cyclooxygenase irreversibly through acetylation, and several groups of organic acids, including proprionic acid derivatives, acetic acid derivatives, and enolic acids, all of which bind to and reversibly inhibit cyclooxygenase. Elimination half-lives (time it takes the body to metabolize half the amount of a substance taken) of these drugs ranges from less than four hours for some proprionic acid derivatives to greater than 40 hours for piroxicam (Feldene®).

In a recent survey by McCormack and Brune of 26 studies investigating the role of NSAIDs in acute soft tissue injuries, 14 double-blind placebo-controlled studies were found to demonstrate a significant difference between NSAID and placebo for nine NSAIDs; clonixin, ketoprofen (Orudis®), naproxen (Naprosyn®), diclofenac (Voltaren®), fenbufen, ibuprofen (Motrin®), indomethacin (Indocin®), piroxicam (Feldene®), and azapropazone (Rheumox). In those studies where physical therapy was also administered, four NSAIDs; azapropazone, clonixin, naproxen, and ketoprofen, were demonstrated to provide unequivocal additional benefit.

Soft Tissue Injuries
In a similar review of investigations of NSAIDs and sports related soft tissue injuries, Weiler concluded that benefits were typically observed amongst treatment groups when compared with controls. These short term studies have found that treated athletes return to practice quicker and without any apparent significant delay in the injury healing process.

In 1987, Amlie et al studied the effects of seven days of oral piroxicam treatment in 278 patients with acute low back pain. Medication administration was commenced within 48-hours of symptom onset and after three days of therapy, patients in the treatment group revealed a significant amount of pain relief. After seven days, the difference in pain symptoms between the treatment and control groups were no longer significant, but the treatment group demonstrated a significantly lower requirement for additional analgesics and a greater return to work rate.

NSAID Choice
The dosing and cost of each NSAID varies significantly by chemical family and agent. (See Table 1, below). The choice of initial anti-inflammatory agent remains largely empirical. Aspirin is generally very inexpensive, and the newer NSAIDs often cost significantly more. In addition to cost considerations, patients have been observed to be more compliant with those agents, which require less frequent dosing.

Table 1. Non-Steroidal Anti-Inflammatory Drugs: Dose and Cost

Since steady states of plasma concentration are not typically observed until dosing has been continued for a period of three to five half-lives, plateau concentrations and maximal therapeutic effects are not realized as quickly in those agents with longer half-lives unless a loading dose is first prescribed. By first prescribing a loading dose, which is not often done in clinical settings, and then maintaining regular dosing as indicated for each agent, adequate plasma levels will be achieved for the anti-inflammatory abilities of these medications to be realized. Prescribing NSAIDs in lower dosages and on a less regular schedule is more likely to utilize only the analgesic properties of these agents. Large variations in patient response to different NSAIDs are observed even when chemically similar drugs of a common family are prescribed. (Over a one- to two-week period the dose may be increased to the recommended maximum, and after that time, if the results remain unsatisfactory, a different agent should be tried.)

Side Effects
Side effects generally develop within the initial weeks of treatment, although gastric complications can develop at later times. Combination therapy with more than one NSAID is to be avoided as the incidence of side effects is additive and there is little evidence of added benefit to the patient. Several complications are associated with NSAID use. As nonselective inhibitors of cyclooxygenase-2 (COX-2), whose activity is induced in the setting of active inflammation, and cyclooxygenase-1 (COX-1), which is responsible for thromboxane (mediates inflammation) and prostaglandin synthesis and the maintenance of normal gastrointestinal mucosa, NSAIDs are commonly observed to alter gastrointestinal physiology. While dyspepsia (upper abdominal discomfort) is a very common complication, erosion, ulceration and hemorrhage may also develop and without warning symptoms. The development of NSAIDs, which selectively inhibit COX-2, would theoretically provide a much safer anti-inflammatory agent.

There is some evidence that nabumetone (Relafen®), which preferentially inhibits COX-2, is associated with a lower incidence of gastrointestinal side effects. Misoprostol (Cytotec®), a synthetic prostaglandin E1 analog, has been shown to reduce the likelihood of gastroduodenal erosion during the administration of aspirin.

As prostaglandins also participate in the autoregulation of renal blood flow and glomerular filtration (renal process, blood is filtered), numerous renal side effects, including acute renal failure, have been associated with NSAID use. The kidneys are most vulnerable in those individuals who might enter a hypovolemic (abnormal low circulating blood volume) state or in whom there is pre-existing renal disease.

While the association between NSAID use and minimal change glomerulonephropathy (inflammation of kidney nerve fibers) has been recognized, a recent study suggests that nephrotic syndrome due to membranous nephropathy should also be recognized as a possible reaction to NSAID use. All NSAIDs can cause central nervous system side effects such as drowsiness, dizziness, and confusion.

Blockade of platelet aggregation, inhibition of uterine contractility, interference with anti-hypertensive medications, and hypersensitivity reactions are also side effects shared by many of the commonly prescribed anti-inflammatory agents. Some variability, with regard to adverse effects, has been recognized amongst the NSAIDs. While the non-acetylated salicylates do not prolong bleeding time and have rarely been associated with gastrointestinal complications, indomethacin has more frequently been associated with nausea, gastrointestinal bleeding, and headaches. NSAIDs have less potential for abuse than opioids; physical dependence on these medications has not been reported.

Recent Studies
Recent studies have investigated the effects of NSAID use upon the healing process of the injured soft tissue, namely muscle and tendon, which they are often prescribed to treat. Almekinders investigated the in vitro effects of indomethacin on isolated human fibroblasts subjected to repetitive motion injury. NSAID use in this study was associated with decreased DNA synthesis during the early proliferative healing phase but with increased protein synthesis during the later remodeling phase of healing.

In an earlier investigation of the effects of piroxicam (Feldene®) on the healing of rat tibialis anterior muscle subjected to strain injury, histological observation revealed a delay in the early inflammatory reactions and regeneration within the muscle tissue of the treated group. At 11 days following injury, though, both treated and controlled groups demonstrated similar extents of regeneration and failure loads. A study investigating the effects of flurbiprofen (Ansaid®) treatment on the recovery of eccentrically injured rabbit muscle revealed treated muscles to demonstrate initial histological and contractile gains but a subsequent functional loss.

The effect of NSAIDs upon chondrocyte (cartilage cell) function and the cartilage matrix has similarly been investigated. As these apparently time dependent effects of NSAID use on soft tissue recovery are further realized, a more scientific approach to the prescription of anti-inflammatory agents will likely arise.

First Line of Defense for Acute Low Back Pain
NSAIDs are a reasonable choice as a first line agent for the control of acute low back pain. The patient is most likely to benefit from their combined analgesic and anti-inflammatory properties during the first week after injury onset. The anti-inflammatory properties of these agents are most likely to be realized when therapy is initiated with a loading dose and the recommended dosages are then continued at regular intervals. The prescribing physician needs to be aware of the adverse effects often associated with NSAID use. Prolonged use of anti-inflammatory medications, i.e. greater than 3-4 weeks, in the setting of acute low back pain is generally not indicated and should be avoided.

Reference: Malanga GA, et al. Pharmacologic Treatment of Low Back Pain. In Physical Medicine and Rehabilitation State of the Art Reviews, Philadelphia, Hanley and Belfus Vol.13, No.3, October, 1999