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Medication and Treatment

An understanding of functional anatomy, biomechanics and kinesiology (study of body movement) can help in localizing the patient's pain generators which include the bone, disc, tendon, muscle, ligament, and nerve. The underlying process can be biomechanical, inflammatory or infectious, neoplastic (i.e. tumor), or psychological in nature.

The answers to these questions will guide the physician toward the proper initial treatment of the low back problem, including the most appropriate choice of medications prescribed. By applying the principles of medication use in other musculoskeletal disorders, we can more strategically plan an efficacious use of pharmacological agents.

In this article, several classes of commonly prescribed drugs for the treatment of low back pain will be considered. For each agent or group of agents considered, mechanisms of action, efficacy and current clinical research, dosing and cost, and complications and contraindications will be discussed.

Acetaminophen
Acetaminophen (Tylenol®) is the principle member of the group of drugs classified as para-aminophenol derivatives. While acetaminophen's analgesic and antipyretic (fever reducing) effects are equal to those of aspirin, its anti-inflammatory effects are weak. Its therapeutic effects appear to be secondary to an inhibition of prostaglandin (mediators of inflammation) biosynthesis with a resultant increase in the pain threshold and modulation of the hypothalamic heat-regulating center (a part of the brain that activates part of the nervous system). The effects of acetaminophen are noted predominantly centrally and less peripherally, were it serves as only a weak inhibitor of cyclooxygenase (enzymes that make prostaglandins) and does not inhibit the activation of neutrophils (acts to clear cell debris), as do other NSAIDs (non-steroidal anti-inflammatory drugs).

As an Analgesic
In the setting of acute low back pain, acetaminophen can be effectively utilized as an analgesic. Several studies have shown acetaminophen to be superior to placebo in the treatment of osteoarthritis pain, and because of its efficacy, it has been recommended as a first line agent in osteoarthritis treatment. A 1991 study by Bradley, et al compared the analgesic properties of acetaminophen to ibuprofen in the treatment of pain associated with osteoarthritis of the knee. Over a four-week study period, acetaminophen was found to be as efficacious as both low dose analgesic and high dose anti-inflammatory regimens of ibuprofen (Motrin®) in providing both pain relief and an improved functional outcome.

In a 1982 study, paracetamol, a compound similar to acetaminophen, was compared to diflunisal (Dolobid®), an NSAID and salicylate derivative (an anti-inflammatory agent), in the treatment of chronic low back pain. Thirty patients with a six-month to several year history of low back pain presumed secondary to facet pathology were treated in a randomized fashion for four weeks, and more favorable outcomes were associated with NSAID use.

Dosage and Side Effects
The accepted oral dose of acetaminophen is 325 to 1000-mg every four to six hours, with a 24-hour use not to exceed 4000-mg. Peak plasma levels and analgesic effects are typically noted from 30 to 60 minutes following ingestion. Acetaminophen is generally available without prescription and is relatively inexpensive.

While erythematosus (skin redness, inflammation) or urticarial skin rashes (multiple raised, swollen, itchy skin areas) are occasionally observed, the most serious adverse affect of acute acetaminophen over dosage is hepatotoxicity (harmful effect on the liver). In adults, hepatotoxicity may result from a single dose of 10 to 15-grams. More chronic abuse of acetaminophen has been associated with nephrotoxicity (harmful effect on the kidneys).

Acetaminophen's analgesic effects make it an acceptable medication in the treatment of acute low back pain. It is inexpensive and its use is typically without complications. While effective against mild to moderate pain in some acute back pain situations, it does not offer the patient other desirable effects against inflammation, muscle spasm, nor sleep disturbance. Its efficacy as an analgesic for low back disorders associated with severe pain is more questionable.

Aspirin
Aspirin is the prototypical member of the group of medications known as non-steroidal anti-inflammatory drugs (NSAIDs). In 1984, nearly one in seven Americans was treated with an anti-inflammatory agent, and in 1986, nearly 100 million prescriptions for NSAIDs were written, resulting in worldwide annual sales estimated at one billion dollars.

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 in files section (Non Steroidal Drugs). 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.

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.

Muscle Relaxants
The muscle relaxing properties of "muscle relaxants" arise not from direct activity at the muscular or neuromuscular junction level but rather from an inhibition of more central polysynaptic neuronal (nerve cells that end in synapses) events. These agents have also been shown in some studies to demonstrate superior analgesia to either acetaminophen or aspirin, and it remains uncertain if muscle spasm is a prerequisite to their effectiveness as analgesics.

Range of Motion
Muscle relaxants are often prescribed in the treatment of acute low back pain in an attempt to improve the initial limitations in range of motion from muscle spasm and to interrupt the pain-spasm-pain cycle. Limiting muscle spasm and improving range of motion will prepare the patient for therapeutic exercise.

Types of Muscle Relaxants
In an attempt to determine the mechanism of action of carisoprodol (Soma®) in the treatment of low back pain, a double blind study was carried out comparing its effectiveness to that of a sedative control, butabarbital (a sedative), and a placebo in the treatment of 48 laborers with acute lumbar pain. Carisoprodol was found to be significantly more effective in providing both subjective pain relief and objective improvements in range of motion when evaluated by finger to floor testing. The results of this study suggest that the effects of carisoprodol are not secondary to its sedative effects alone.

In 1989, Basmajian compared the effectiveness of cyclobenzaprine (Flexeril®) alone with diflunisal (Dolobid®), placebo, and a combination of cyclobenzaprine and diflunisal in the treatment of acute low back pain and spasm. During the ten-day study period, the combined treatment group demonstrated significantly superior improvements in global ratings on day four, but not on day two or seven. This study suggested some effectiveness of combined analgesic and muscle relaxant therapy when utilized early in the initial week of pain onset.

Borenstein compared the effects of combined cyclobenzaprine and naproxen (Naprosyn®) with naproxen alone and also found combination therapy to be superior in reducing tenderness, spasm, and range of motion in patients presenting with ten days or less of low back pain and spasm. Adverse effects, predominantly drowsiness, were noted in 12 of 20 in the combined group and only four of 20 treated with naproxen alone.

Cyclobenzaprine and carisoprodol were compared in the treatment of patients with acute thoracolumbar pain and spasm rated moderate to severe and of no longer than seven days duration. Both drugs were found to be effective, without significant differences between the treatment groups. Significant improvements were noted in physician rated mobility and in patients' visual analogue scores on follow up days four and eight. While 60% of patients experienced adverse effects in the form of drowsiness or fatigue, these differences were not significantly different between groups, and only eight percent of patients from each group discontinued treatment.

Baratta found cyclobenzaprine, 10-mg t.i.d. (three times per day), superior to placebo in a randomized, double blind study of 120 patients with acute low back pain presenting within five days of symptom onset. Significant improvement was noted in range of motion, tenderness to palpation, and pain scores on follow up days two through nine. Sixty percent of treatment group patients reported drowsiness or dizziness compared with 25% of those in the placebo group.

In an earlier study, diazepam (Valium®) was found to offer no significant subjective or objective benefit, when compared to placebo, in patients treated for low back pain. Carisoprodol was found to be superior to diazepam in the treatment of patients with "at least moderately severe" low back pain and spasm of no longer than seven days duration. In this study, the overall incidence of adverse reactions was higher in the diazepam treated group but was not of statistical significance.

Origin of Muscle Spasm
Muscle spasm of local origin needs to be clinically differentiated from spasticity and sustained muscle contraction in the setting of the central nervous system (CNS) and upper motor neuron injury. Baclofen (Lioresal®) and dantrolene sodium (Dantrium®) are two agents whose use is indicated in the setting of spasticity of CNS etiology. Dantrolene sodium is of particular interest, as its mechanism of action is purely at the muscular level where it serves to inhibit the release of calcium form the sarcoplasmic reticulum.

Casale studied the effectiveness of dantrolene sodium, 25-mg daily, in the treatment of low back pain and found patients to demonstrate significant improvements in visual analogue scores, pain behavior, and electromyographic (EMG) evaluations of "antalgic reflex motor unit firing," when compared with the placebo group. The findings of this study are interesting in that they demonstrate improvement secondary to a pure muscle relaxant, which does not possess other outside anti-nociceptive properties.

Baclofen is a derivative of gamma-aminobutryic acid (GABA) and is believed to inhibit mono and polysynaptic reflexes at the spinal level. Treatment with baclofen was compared to placebo in a double blind, randomized study of 200 patients with acute low back pain. Patients with initially severe discomfort were found to benefit from baclofen, 30- to 80-mg daily, on days four and ten of follow up. Forty-nine percent of treatment patients complained of sleepiness, 38% of nausea, and 17% discontinued treatment.

Sedation: Side Effect
Sedation is the most commonly reported adverse effect of muscle relaxant medications. These drugs should be used with caution in patients driving motor vehicles or operating heavy machinery. More absolute contraindications do exist to the use of carisoprodol, cyclobenzaprine, and diazepam. Rare idiosyncratic reactions have also been reported to carisoprodol and its metabolites such as meprobamate. Benzodiazepines have potential for abuse and their use should be avoided. By initially prescribing muscle relaxants at bedtime, the physician might take advantage of their sedative effects and minimize daytime drowsiness.

These agents have been found to be effective when used either alone or in combination with an analgesic/anti-inflammatory agent within seven days of symptom onset. The prescribing physician should monitor patients receiving these medications and tailor dosages in an attempt to minimize the drowsiness and sedation often associated with their use. The use of benzodiazepines does not appear to offer any significant benefit to patients experiencing acute low back pain. Further research is needed before the role of baclofen and dantrolene sodium in the treatment of muscle spasm of local origin can be more clearly defined.

Opioids
Opioids occupy the second rung on the World Health Organization (WHO) analgesic ladder in the treatment of moderate to severe cancer pain and are commonly prescribed for postoperative pain, where they have been found to successfully treat both local and more generalized pain symptoms.

Opioid drugs produce analgesia by binding to multiple types of opioid receptors, which are typically bound by endogenous opioid compounds. These receptors are generally classified as mu, kappa, and delta, but the opioid medications typically prescribed are morphine-like agonists, which occupy the mu receptor. These receptors are located both peripherally, on sensory nerves and immune cells, and centrally, in the spinal cord and brainstem.

In a study by Brown et al, the analgesic efficacy of diflunisal (Dolobid®), 500-mg p.o. b.i.d. (by mouth, twice a day) following a 1000-mg loading dose was compared to that of 300-mg of acetaminophen with 30-mg of codeine in the treatment of pain resulting from initial or recurrent low back strains. Over this 15-day trial, the analgesic efficacy each regimen was found to be similar, but patient acceptability and tolerance were found to be superior for diflunisal. Five of 21 patients treated with acetaminophen and codeine reported adverse effects including drowsiness, dizziness, fatigue, and nausea, compared with three of 19 patients treated with diflunisal.

In a study of 200 patients presenting with acute low back strain, Weisel et al compared the analgesic efficacy of acetaminophen with codeine and aspirin plus oxycodone (i.e. OxyContin). While all analgesic medications considered were not shown to result in a more prompt return to work, a significantly greater pain reduction, especially within the first three days of treatment, was noted for those individuals treated with codeine or aspirin plus oxycodone.

Peak Drug Effect
For most opioids, peak drug effect occurs within one- and one-half to two-hours following oral administration, and a second opioid dose can safely be taken two-hours after the first if side effects are mild at that time. Sustained-release tablets are also available and often prove beneficial in those patients with more rapidly fluctuating pain. The potency of the opioid agonists is generally compared with that of morphine.

Tramadol hydrochloride (Ultram®) is a newer centrally acting analgesic, which, although not chemically related to opiates, binds to mu receptors. Its mechanism of action is not completely understood, but is felt to be at least in part secondary to its inhibition of the reuptake of both serotonin and norepinephrine. Tramadol has been demonstrated to provide superior analgesia to combined acetaminophen-propoxyphene (i.e. Darvocet®) in patients experiencing severe postoperative pain, and similar analgesia, but with greater tolerability, to morphine in patients hospitalized for cancer pain.

In a four-week study of 390 elderly patients with chronic pain secondary to a variety of conditions, tramadol was found to provide comparable analgesia to acetaminophen with codeine without a significant difference in associated adverse effects. Additional studies reveal the low abuse potential and the absence of significant respiratory depression associated with tramadol use. Individualization of tramadol dosage is recommended for those individuals either over 75 years of age, with impaired renal function, and with significant liver disease.

Achieving Balance
The goal of successful opioid prescription involves achieving a tolerable balance between analgesia and the side effects often associated with opioid use. Tolerance to adverse effects such as somnolence (sleepiness), nausea, and impaired thought processes typically occurs within days to weeks of initial opioid administration. Constipation is a more persistent side effect, which can be managed with stool softeners and laxatives. Normeperidine, a metabolite of meperidine (Demerol®), accumulation with repetitive dosing has been associated with the development of anxiety, tremors, myoclonus (muscle spasm) and generalized seizures; patients with impaired renal function are at particular risk. Methadone (Dolophine®) demonstrates good oral potency and a plasma half-life of 24-36 hours. Accumulation of methadone may occur with repetitive dosing, resulting in excessive sedation on days two to five. Physical dependence can develop after several days of administration of opioid analgesics.

When Properly Used
Despite the stigmas and fears of addiction associated with their use, when properly utilized by a knowledgeable physician, opioid analgesics successfully treat otherwise intractable pain. The potential role of opioids in the treatment of non-malignant acute low back pain is limited; reserved for those patients who have either failed to realize adequate analgesia from alternative medications, i.e. NSAIDs plus or minus a muscle relaxant, or who have contraindications to the use of other analgesics. The use of opioids in the treatment of low back pain should be limited to pain that is unresponsive to alternative medication, such as appropriately prescribed NSAIDs or when contraindications exist to the use of other analgesics. Opiates may appropriately be prescribed in the case of an acute disc herniation or other back injury in order to faciliate restoration of function and reduce unwanted compensatory strategies. When prescribed, opioids should be used on a defined dosing schedule and not on a p.r.n. (as needed) basis. Chronic opioid treatment may be an option in selected patients who have failed all other treatments. These patients should be monitored for appropriate medication use on regular intervals.

Corticosteroids
Oral steroids have been found effective in the treatment of inflammatory reactions associated with allergic states, rheumatic and autoimmune diseases, and respiratory disorders. Corticosteroids interact with receptor proteins in target tissues to regulate gene expression and ultimately protein synthesis by the target tissue. As these interactions and regulatory processes occur slowly, most of the effects of corticosteroids are not immediate and become apparent hours following their introduction. Recent investigations have suggested an additional and more immediate component to corticosteroid action mediated by an interaction with membrane-bound protein receptors.

Over the past two decades, the biochemical contributions to sciatica and low back pain have been the focus of much attention. In the late 1970's the nuclear material of the vertebral disc was found to be antigenic and capable of producing an in vitro autoimmune reaction. It was hypothesized that a chemical radiculitis might explain radicular pain in the absence of a more mechanical stressor.

Phospholipase A2 (PLA2), a potent inflammatory mediator, has demonstrated to be released by discs following injury. The anti-inflammatory and immunosuppressive effects of glucocorticoids are largely secondary to their inhibition of the immune responses of lymphocytes, macrophages, and fibroblasts. Whereas NSAIDs principally inhibit prostaglandin synthesis, corticosteroids interfere earlier in the inflammatory cascade by inhibiting PLA2 actions and thereby curtailing both the leukotriene and prostaglandin mediated inflammatory response.

Studies: Steroids and Acute Low Back Pain
Studies designed to investigate the use of oral steroids in the setting of acute low back pain are limited. In 1986, Haimovic and Beresford compared oral dexamethasone (Decadron®) with placebo in the treatment of 33 patients with lumbosacral radicular pain. Subjects receiving dexamethasone were given a tapering dose, from 64- to 8-mg over seven days. Early improvements (within seven days) were not significantly different between the two groups, occurring in seven of 21 patients in the dexamethasone group and four of 12 in the placebo group.

In those subjects initially found to have radicular type pain on straight leg-raising, however, eight of 19 treated with dexamethasone, compared with only one of six in the placebo group, had diminished pain on straight leg raising repeated within seven days. The limitations of this study include a small subject number, the use of additional analgesics, which may have obscured group differences, the clinical uncertainty of a radicular process in a significant number of subjects, and the loss of several patients to follow up after one year.

Adverse Effects
In the setting of acute low back pain with radiculopathy, oral corticosteroids are typically prescribed in a quick tapering fashion over one week. Multiple adverse effects have been associated with prolonged steroid use, including suppression of the hypothalamic-pituitary-adrenal axis, immunosuppression, psuedotumor cerebri and psychoses, cataracts and increased intraocular pressure, osteoporosis, aseptic necrosis, gastric ulcers, fluid and electrolyte disturbances and hypertension, and impaired wound healing.

The severity of these complications correlates with the dosage, duration of use, and the potency of the steroid prescribed. While the incidence of steroid-induced myopathy does not appear to be directly related to the dosage of steroid prescribed nor the duration of use, it appears to be more prevalent with the use of steroids containing a 9-alpha fluorine configuration, such as triamcinolone (Aristocort®). The relationship between hypertensive side effects and the duration of therapy is also not very clear; steroids should be prescribed with greater caution in the elderly, in those individuals with known hypertension, and when compounds with greater mineralocorticoid properties are prescribed. As hyperglycemia is a well-known complication of corticosteroid use, oral steroids should be prescribed with caution in the diabetic population.

As potent anti-inflammatory agents, oral steroids represent a theoretically useful agent in the treatment of patients with radiculopathy due to local inflammation secondary to disc injury or herniation. While many adverse effects are associated with oral steroid use, these are more frequently encountered in the setting of prolonged administration. The effectiveness of oral steroids in the acute low back pain population remains unproven; further research in this area is needed.

Colchicine
Colchicine has been regarded by some as the most powerful anti-inflammatory agent known to man. The beneficial effects of colchicine in the treatment of gout are apparently secondary to its ability to inhibit both the metabolic and phagocytic activity and migration of granulocytes. Colchicine's inhibition of the release of histamine containing granules from mast cells is also believed secondary to its interference with granule transportation by the microtubular system. While beneficial in the treatment of the crystal-induced inflammation observed in gout and pseudogout, colchicine is only occasionally effective in the treatment of other types of arthritides (arthritis).

Resistant Disc Disorders
Over the past 30 years, Rask has treated thousands of patients with resistant disc disorders with oral and intravenous colchicine and has noted a 90-95% improvement rate. Since 1979, he has published the results of his uncontrolled studies, some involving up to 500 patients, who have suggested significant therapeutic benefits from colchicine therapy with fewer adverse effects than typically associated with the use of aspirin.

In a 1985 double blind study of 39 patients with low back pain of at least two months duration, Meek compared combined intravenous and oral colchicine treatment with placebo. Patients in the treatment group received colchicine .6-mg orally b.i.d. (twice a day) for 14 days and one-mg IV (intravenous) on days one, four and eight of the 14 day study period.

Adverse Effects
While no real effect from placebo administration was observed, the treatment group demonstrated significant improvements in pain, weakness, leg raising limitations, and muscle spasm. Adverse effects from colchicine administration were documented in only one patient in the form of a burn at the IV site. In a double blind study of oral colchicine in the treatment of low back pain, Schnebel and Simmons compared oral colchicine with placebo in 34 patients with low back symptoms of less than three months duration. Over the 12-week study period, both groups of patients continued in a comprehensive physical therapy program and were administered NSAIDs and muscle relaxants. No significant differences in therapeutic response were noted between the treatment and placebo groups, but an increased number of adverse effects, mainly diarrhea and vomiting, were observed in the colchicine group. This study has several limitations, including a small sample size, multiple etiologies of low back pain, poor patient compliance, and the use of concomitant treatments.

Contraindications
Colchicine use is contraindicated those patients with serious gastrointestinal, renal, hepatic or cardiac disease. Colchicine can also harm the fetus when used during pregnancy. When administered intravenously for the treatment of an acute gouty attack, the total dosage over the first 24-hours should not exceed four milligrams, as greater cumulative dosages have been associated with multiple organ failure and death.

Abdominal pain, nausea, vomiting, and diarrhea, are typically the earliest and most common adverse effects associated with colchicine over dosage. These gastrointestinal side effects can be almost entirely avoided with intravenous use. Colchicine has also been noted to cause a transient leukopenia (abnormal decrease in the number of white blood cells), which is soon replaced with a leukocytosis (abnormal increase in the number of white blood cells). Myopathy and neuropathy have been noted in patients with impaired renal function receiving colchicine treatment.

Colchicine and Low Back Pain
The use of colchicine in the treatment of the acute low back pain patient is not commonly practiced. While some practitioners have found colchicine effective in this patient population, others have not. Further investigation in this area is needed before colchicine use can be recommended for the low back pain patient. These studies may be helpful in further defining colchicine's place among other available anti-inflammatory and analgesic agents.

Anti-Depressant Medications
While several classes of anti-depressants have been used successfully in the treatment of a variety of pain syndromes, the literature most strongly supports the analgesic efficacy of the tricyclics (anti-depressant drug). Amitriptyline (a type of anti-depressant) has been investigated as an analgesic more than the other anti-depressant agents and appears to be the most popular anti-depressant analgesic in the clinical setting. Migraine headaches, neuropathic pain associated with diabetic neuropathy, and postherpetic neuralgia have been found to respond favorably to anti-depressant administration.

These agents have also been found to alleviate the pain associated with musculoskeletal conditions such as fibromyalgia, rheumatoid arthritis, and osteoarthritis. Anti-depressants have been successfully utilized in the treatment of cancer pain. In the cancer population, when administered concurrently with an anti-depressant, opioid agents may be used at a reduced dose and with a diminished incidence of side effects.

The analgesic abilities of anti-depressants were once felt to be related to the alleviation of the depression, which can often accompany persistent pain, but several anti-depressants have been found to reduce pain symptoms in patients not experiencing co-morbid depression. These agents are now believed to have primary analgesic abilities, which are most likely related to their effects on monoamines in endogenous pain pathways. The efficacy of both serotonin and norepinephrine selective anti-depressants would suggest that effects on pathways which involve either of these transmitters might contribute to analgesia. Other suggested mechanisms of analgesia involve the antihistamine properties of some agents, increased endorphin secretion, and an increased density of cortical calcium channels.

In a study of 44 patients admitted for low back pain, Jenkins et al compared treatment with oral imipramine (Tofranil®), 25-mg t.i.d. (three times per day), with placebo over a four-week period. After treatment, no significant difference in improvement in straight leg raising, pain and stiffness assessments, nor psychological testing was noted between the two study groups. In those individuals with apparent discogenic pain, imipramine treated patients demonstrated greater improvement in pain and stiffness, but this was not found to be statistically significant. No significant difference in side effects was noted between the two groups.

In a study of 48 patients with chronic low back pain, treatment with imipramine was compared to placebo. Seven of the patients included were determined clinically depressed according to standard criteria. Patients completed Beck depression questionnaires at both the initial and final visits. Depression score improvements, while not statistically significant, were noted in those patients who benefited from imipramine treatment. Individuals treated with imipramine did demonstrate a significant improvement in both limitations of work and restrictions in normal activities. Anticholinergic side effects were associated with a 10% dropout rate.

In a review of the literature on anti-depressants in the treatment of chronic low back pain, Egbunike et al concluded that the most consistent responses were found with doxepin (Sinequan®) and desipramine at doses above 150-mg daily. Some studies may have failed to demonstrate a response secondary to inadequate dosing. Other anti-depressants were found less effective in providing analgesia. In several studies reviewed, while improvements in depression were observed, poor correlations were noted between analgesic effects and changes in the severity of depression. The relationship between pain relief and anti-depressant effect remains unclear.

Dosage
Tricyclic anti-depressants (TCAs) produce analgesia at lower dosages than are typically prescribed for the treatment of depression. The starting dose of the tricyclics should be low. Initial daily dosing of amitriptyline should be 10-mg in elderly patients and 25-mg in younger individuals. Every two to three days an increment in dosing equal to the initial starting dose can be made until adequate analgesia is achieved or adverse effects develop.

The typical effective daily dose of amitriptyline ranges from 50- to 150-mg, although doses as low as 10-25-mg can be helpful in some patients. As the TCA half-life is generally long and sedation is a common side effect, single nighttime dosing can be prescribed. Some patients report better pain relief and less morning drowsiness with divided daily dosing. Those studies, which have investigated the analgesic efficacy of selective serotonin reuptake inhibitors (SSRIs), have typically involved dosages similar to those prescribed in the management of depression, 20- to 40-mg of fluoxetine or paroxetine. Further research is needed in order to clarify the relationship between dosage and analgesia with the serotonin specific agents.

Adverse Effects
The occurrence of serious adverse effects resulting from antidepressant administration is low. These complications would be rare at the generally lower dosages utilized in the treatment of pain. While cardiac side effects are uncommon, tricyclics are contraindicated in those individuals with heart failure or serious cardiac conduction abnormalities. Orthostatic hypotension is the most frequent cardiovascular adverse effect, and the elderly are particularly at risk. The sedating effect often observed with anti-depressant use can be beneficial as patients with pain often demonstrate diminished daytime functioning from inadequate sleep.

Anticholinergic side effects such as dry mouth, blurred vision, and urinary retention are more likely with amitriptyline use than with other TCAs. These effects are also less likely at the lower dosages used for analgesia. Nortriptyline and desipramine have been found to induce fewer anticholinergic side effects and are less sedating.

While anti-depressants have been demonstrated as useful adjuncts in the treatment of pain, their analgesic mechanism remains unclear. Initial dosing should be low and then slowly increased to minimize side effects. When taken at night, the sedating properties of these agents can be beneficial in those pain patients experiencing difficulty with sleep.

Conclusion
There are various agents that can be helpful in addressing the painful phase of acute low back problems. The particular medication should be chosen after consideration of the following: (1) indications (2) contra-indications (3) goals of treatment, i.e. analgesia, reduction of inflammation, reduction of muscle spasm, etc., and (4) the scientific and clinical evidence of there effectiveness.

With the proper selection of pain medication and a positive response, the patient can then be progressed through more active rehabilitation and avoid the development of a more chronic condition.