Efficacy of transdermal nitroglycerin combined with etodolac for the treatment of chronic post-thoracotomy pain: An open-label prospective clinical trial

1. Introduction 

Thoracotomy may be followed by persistent pain. This entity, chronic post-thoracotomy pain (CPP), is characterized by pain that is generally burning and aching, localized in the incisional area, and persists for more than two months.1 The incidence of CPP may be as high as 80%.2 Dajczman et al.3 reported that 73% of patients continued to complain of pain 2 years after thoracotomy. Although the pain is moderate in most cases, it interferes with daily activities in almost 50% of affected patients.2., 3.

Pathogenetically, CPP is associated with intercostal nerve injury.4., 5. Like other forms of neuropathic pain, treatment is difficult and unsatisfactory5., 6. and has a high rate of unpleasant side effects, making compliance very poor.7

Several studies have reported excellent results in the treatment of acute pain with minimal side effects using transdermal nitroglycerin (NTG).8., 9., 10. The aim of the present prospective study was to evaluate the effect of transdermal NTG combined with the nonsteroidal anti-inflammatory drug (NSAID) etodolac on chronic pain after thoracotomy in patients who failed to respond to etodolac alone.

2. Methods 

The study protocol was approved by the Institutional Ethics Committee, and all patients provided informed consent before entering the study. The records of all adult patients who underwent thoracotomy at our institution between January 2000 and July 2001 were reviewed, and the patients were interviewed by telephone. Those who reported pain compatible with CPP were invited to attend our pain clinic. Chronic post-thoracotomy pain was defined as spontaneous; burning or aching; in or around the area of surgical incision; with or without paresthesia, allodynia, or hyperalgesia; and present for more than two months. Patients with a pain intensity grade of ≥60 mm on a 100 mm visual analog scale (VAS) were enrolled in the study. Patients with sensitivity to nitrates, skin disease that prevented the use of transdermal drugs, cerebrovascular disease or aortic stenosis, and patients regularly receiving nitrates or other vasodilators were excluded.

Having enrolled in the study, patients received etodolac (Etopan, Taro, Israel) 400 mg every 8 hr for two weeks. If pain relief was unsatisfactory (<25% reduction in VAS), a patch of transdermal NTG (Deponit 5, Schwarz Pharma AG, Monheim, Germany), 5 mg per day, was added to the NSAID regimen. The patch was applied on hair-free skin for 14 days. Patients were evaluated for pain intensity on the VAS, breakthrough pain (intensity and number of daily attacks), and sleep efficiency (percent of sleeping hours/time in bed) on days 1, 2, 7, and 14 after beginning treatment. Side effects were recorded.

An independent observer, who was blinded to the patient's identity and clinical course, evaluated the data. Data are given as means±standard errors and were analyzed by ANOVA; P<0.05 was considered significant.

3. Results 

Of the 129 patients interviewed from three months to a year and a half after thoracotomy, only 25 (19.3%) were pain-free, and 104 had chronic post-thoracotomy pain. Of the latter, 39 had pain graded ≥60 mm on the VAS scale. This subgroup of patients was enrolled in the study. Etodolac alone yielded a clinically significant improvement in pain intensity in 9 patients (23%). The remainder (n=30) received adjunctive treatment with NTG.

The study group (etodolac and NTG) consisted of 18 men and 12 women. Mean age was 59±13 years. Mean time after thoracotomy was 9.8±5 months. Mean VAS score at the beginning of NTG treatment was 66.7±11 mm.

No significant changes in pain intensity were recorded during the first week of NTG administration. On day 14, mean VAS grade dropped to 42.1±5 mm (P<0.05), representing a 37% reduction in pain intensity (Figure 1). A similar change was noted in breakthrough pain on day 14, from VAS 84.7±8 mm to 60.5±3 mm, P<0.05 (Figure 2). The number of daily attacks was reduced as well, from 4±1 to 3±1, although this difference was not statistically significant. Sleep efficiency significantly improved in the second week of NTG treatment, from 58.2±12% to 82.6±4% sleep hours/time in bed, P<0.05 (Figure 3).

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Fig. 1. Intensity of pain in patients with chronic post-thoracotomy pain treated with etodolac alone (Etodolac) and with NTG patch and etodolac (NTG). No clinical improvement was evident after 2 weeks of treatment with etodolac alone (400 mg every 8 hr). After 2 weeks of adjunctive treatment with NTG patch (5 mg per day), significant improvement was observed, from basal VAS 66.7±11 to VAS 42.1±5. ∗P<0.05.

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Fig. 2. Intensity of breakthrough pain in patients with chronic post-thoracotomy pain treated with etodolac alone (Etodolac) and with NTG patch and etodolac. No clinical improvement occurred after 2 weeks of treatment with etodolac alone (400 mg every 8 hr). After 2 weeks of adjunctive treatment with NTG patch (5 mg per day), the intensity of breakthrough attacks significantly decreased from severe pain (VAS 84.7±8) to moderate pain (VAS 60.5±3). ∗P<0.05.

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Fig. 3. Effect of etodolac alone (Etodolac) and NTG/etodolac (NTG) on sleep efficiency (% sleep hr /time in bed). No clinical improvement occurred after 2 weeks of treatment with etodolac alone. After 2 weeks of adjunctive treatment with NTG patch, sleep efficiency improved from a mean of 58.2±12% to 82.6±4%. ∗P<0.05.

The only side effect was mild headache, recorded in 66% of the men and 83% of the women. It abated spontaneously in most cases within 48 hr after initiation of NTG treatment. There was no need to discontinue NTG because of headache.

4. Discussion 

In agreement with previous reports,2., 3. we found a high rate of chronic pain in patients after thoracotomy. Regular administration of etodolac was ineffective in 77% of these with a VAS grade of ≥60 mm and additional transdermal NTG provided significant pain relief in this group of patients.

To the best of our knowledge, this is the first time NTG has been evaluated clinically for the treatment of chronic pain with neuropathic characteristics. Previous reports have documented a synergistic action of NTG with opioids9 and with spinal neostigmine.10 However, the combination of NTG and NSAIDs has not been previously investigated.

Nitroglycerin is metabolized to nitric oxide (NO) in the cell. Although effectiveness of NTG as an anti-inflammatory and analgesic agent has been attributed to the release of NO,8., 9., 10. the role of NO in neuropathic pain is still controversial. NO causes an increase in the intracellular concentration of cyclic guanosine monophosphate (cGMP), which produces pain modulation in the central and peripheral nervous system.11., 12., 13. In the spinal cord, studies in a rat model of neuropathic pain have shown that NO exerts an analgesic action and attenuates allodynia.14., 15. Some researchers proposed that the release of NO in the spinal cord also plays an important role in the analgesic effect of intrathecal clonidine on neuropathic pain.16 Further support for the analgesic and anti-inflammatory effects of topical NTG were provided by the decreases in pain noted in an experimental model of prostaglandin E2-induced hyperalgesia.17

Conversely, however, up-regulation of nitric oxide synthase, with the consequent NO overproduction, has been implicated in the pathophysiology of neuropathic pain.18

To explain this discrepancy, some recent reports suggest that NO affects pain modulation in a dose-related manner. Accordingly, Prado et al.19 observed that local application of low-dose NO donors reduced incision allodynia in rats, whereas another cream that released 10- to 20-fold more NO intensified the pain.19 This dual effect of NO was also reported in rats with neuropathic pain. Low intrathecal doses of NO donor reduced allodynia, while higher doses increased the pain.20

The clinical efficacy of transdermal NTG for acute pain relief has been documented in several studies. NTG was found to be useful for the treatment of shoulder pain,8 for reducing oral analgesic requirements in patients with pain due to thrombophlebitis,21., 22. and for enhancing the effect of spinal sufentanil for postoperative analgesia.9 Transdermal formulations of NTG have several advantages for chronic use: simplicity of administration, lack of variability in drug availability due to differences in gastrointestinal absorption, and lack of gastrointestinal irritation.

The potential synergism of NTG and the NSAID etodolac is suggested by the fact that the two drugs act at different locations along the pain pathway.23 The NSAID etodolac acts mainly at the periphery,24 whereas the NO released by NTG exerts its effect mainly on neurotransmission of pain.11., 12., 13., 14., 15., 16.

The design of the present study precludes conclusions regarding the additive or synergistic effect of NTG and etodolac. Nevertheless, their simultaneous use has clinical significance because it considerably improved patient compliance. In our previous pilot study using NTG alone, a high incidence of severe headache interfered with treatment acceptance. In the present study, the only side effect reported by our patients was mild headache, which was self-limited to the first days of treatment.

Analgesia become evident in our study only in the second week of NTG treatment, unlike the immediate effect reported in earlier studies in patients with acute pain using transdermal NTG at the same doses.8., 9., 10. The reason for this difference is not clear, but it probably involves the plastic and functional changes related to neuromodulation associated with chronic pain.

One of the limitations of our study is the lack of a placebo group. Although the improvement might be accounted for in part by a placebo effect, the delayed response makes this possibility unlikely.

We conclude that transdermal NTG added to an oral NSAID appears to be effective and well-tolerated in patients with chronic pain after thoracotomy. This study provides background for further randomized, blinded trials of NTG in this patient population.