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Low-Dose Tricyclic Antidepressants May Be Effective in Treating Chronic Lower Back Pain if Other Analgesics Fail

Patients with chronic lower back pain (CLBP) are often treated with NSAIDs (nonsteroidal anti-inflammatory drugs), muscle relaxants, simple analgesics or opioids. However, for many, these medications do not sufficiently relieve their CLBP.

Since CLBP can usually be divided into two types of pain, nociceptive (pain from tissue injury) or neuropathic (pain from nerve injury), physicians have often tried using off-label medications to manage the neuropathic pain, while avoiding them for nociceptive pain.

The medications used as adjunctive pain medications include those used to treat depression: tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs), as well as anti-epileptic medications.

The theories regarding how these medications work depends on the medication itself. For example, capsaicin cream and anti-inflammatories work on blocking the activity of inflammatory pain enzymes. Medications like gabapentin and pregabalin can block a windup phenomenon with the dorsal horn increasing activity of N-methyl-o-aspartate receptors and voltage-gated calcium channels.

When looking at the use of TCAs and SNRIs, they may enhance the descending inhibition of pain pathways depressed at the spinal cord level by increasing levels of the neurotransmitters serotonin and norepinephrine. Carbamazepine may make nerves less excitable.

There are several types of TCAs, which work on different structural levels. Action of SSRIs appears to be that the medications address the emotional disturbances that may relate to neuropathic pain. SNRIs, however, affect both serotonergic and noradrenergic pathways. Antiepileptics began due to the FDA approval for their use in postherpetic neuropathy (PHN), and diabetic peripheral neuropathy (DPN). The first-generation antiepileptics are thought to act by inhibiting voltage-gated sodium channel and maybe stabilizing the effect on neuronal membranes. Carbamazepine, a first-generation antiepileptic requires close monitoring of blood levels because of its narrow therapeutic window.

Second-generation antiepileptics, such as gabapentin, inhibit excitatory neurotransmitter release. It requires a slow titration to therapeutic levels. Third-generation antiepileptics, such as pregabalin, acts at a voltage-gated calcium channel, much like gabapentin. Topiramate, on the other hand, is thought to block voltage-dependent sodium channels and inhibit excitatory neurotransmission, as well as potentiate GABA transmission. Finally, lamotrigine appears to work through sodium blockade and neural membrane stabilization.

No antiepileptics are FDA-approved nor demonstrated by clinical trial for use for CLBP, however many physicians do use them off-label to manage primarily neuropathic or radicular pain. Carbamazepine is approved for neuropathic states and gabapentin is approved for PHM. Pregabalin is approved for PDN and PHN. Phenytoin has no FDA approval for neuropathic pain, but has been found effective for treatment of trigeminal neuralgia.

Antidepressants do not have many studies to back up their use in pain control in CLBP, however, there have been studies done for neuropathic pain. These conditions include painful polyneuropathy, PHN, central poststroke pain, and postmastectomy pain.

The authors of this study reviewed various analyses and trials to determine the usefulness of the above-mentioned medications in treating CLBP. This is what they found:

- Neuropathic pain and antidepressants: relieved over several weeks of treatment independent of any antidepressant effect.
- 30 percent of patients given antidepressants experienced more than 50 percent of pain relief
- comparing various TCAs among each other was difficult because of the different dosages in the studies, the titrations, and study end points.
- Venlafaxine appeared to provide a higher success rate in symptom improvement than did imipramine for patients with PPN.
- Venlafaxine was superior to placebo in treatment of neuropathic pain following breast cancer, despite low doses.
- Duloxetine, through several randomized,controlled trials, has shown improvement of major depressive disorders and improvement in overall neck and back pain.
- The FDA has approved duloxetine for DPNP.
- There is limited evidence to evaluate the efficacy of antiepileptics for the relief of radicular or neuropathic CLBP.
- Carbamazepine has not been evaluated for CBBP or radiculary symptoms.
- Gabapentin has not been evaluated formally for treatment of CLBP.
- No studies have been done to specifically evaluate topiramate for CLBP, however in one study, researchers concluded that topiramate (200 mg mean dose) do provide a small but real analgesic effect on CLBP.
- A small study round that lamotrigine did reduce sciatic pain.
- No meaningful clinical evidence exists for the use of valproic acid, felbamate, and zonigran.

As with all medications, the issue of side effects is an important one. When using TCAs for CLBP, doctors must take into account the typical side effects of blurred vision, cognitive changes, dry mouth, constipation and sexual dysfunction. TCAs should be used with caution in patients with glaucoma, urinary retention, or autonomic neuropathy, as well as patients with orthostatic hypotension and cardiovascular problems.

With SNRIs, venlafaxine appears to be the less tolerated of the group, with side effects of nausea, sexual dysfunction, an withdrawal problems. Side effects of duloxetine include nausea, somnolence, hyperhidrosis, anorexia, and constipation.

When patients are given antiepileptics, side effects of carbamazepine can include Steven-Johnson syndrome, agranulocytosis, aplastic anemia, and hepatic toxicity. Gabapetin side effects include dizziness, somnolence, peripheral edema, weight gain, and vertigo.

In conclusion, the article authors state that the evidence that supports the use of adjunctive medications for CLBP is limited but appears reasonable in low doses, if acetaminophen and NSAIDs have not been appropriate treatments.

Victor Chang, MD, Peter Gonzalez, MD, and Venu Akuthota, MD. Evidence-informed management of chronic lower back pain with adjunctive analgesics. In The Spine Journal. January/February 2008. Vol. 8. Issue 1. Pp. 21-27.


*Disclaimer:* The information contained herein is compiled from a variety of sources. It may not be complete or timely. It does not cover all diseases, physical conditions, ailments or treatments. The information should NOT be used in place of visit with your healthcare provider, nor should you disregard the advice of your health care provider because of any information you read in this topic.
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