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REGIONAL ANESTHESIA AND PAIN MEDICINE

The Response of Neuropathic Pain and Pain in Complex Regional Pain Syndrome I to Carbamazepine and Sustained-Release Morphine in Patients Pretreated with Spinal Cord Stimulation: A Double-Blinded Randomized Study

Department of Anesthesia and Pain Therapy, Klinikum Krefeld, Krefeld, Germany.

Address correspondence and reprint requests to Henning Harke, MD, Department of Anesthesia and Pain Therapy, Klinikum Krefeld, Lutherplatz 40, D-47805 Krefeld, Germany.

	Abstract

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Forty-three patients with peripheral neuropathic pain, exclusively pain reduced by spinal cord stimulation (SCS), were switched into a painful state after SCS inactivation. This mode was used to assess the pain-relieving effect of carbamazepine (CMZ) and opioids in a double-blinded, placebo-controlled trial. In Phase 1, the patients were randomly allocated to receive either CMZ (600 mg/d) or placebo during an SCS-free period of 8 days. In Phase 2, after a CMZ elimination interval of 7 days, 38 patients received either sustained-release morphine (90 mg/d) or placebo for 8 days. In cases of intolerable pain, the patients were authorized to reactivate their SCS. The pain intensity was rated on a numeric analog scale. In 38 patients who completed Phase 1, significant delay in pain increase was observed in the CMZ group as compared with placebo (P = 0.038). In Phase 2, the trend observed with morphine was insignificant (P = 0.41). Two CMZ patients and one morphine patient showed complete pain relief and preferred to continue the medication. Thirty-five patients returned to SCS. We conclude that CMZ is effective in peripheral neuropathic pain. Morphine obviously requires larger individually titrated dosages than those used in this study for results to be adequately interpreted.

Implications: This study included patients with neuropathic pain suppressed by spinal cord stimulation (SCS). After deactivation of SCS, different drug effects were evaluated. In contrast to morphine, carbamazepine showed significant pain relief compared with placebo.

	Introduction

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Peripheral neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the peripheral nervous system (1). Nerve damage generates ectopic discharges, which create specific sensitizing mechanisms in dorsal horn neurons involving the following: first, constant drive of input maintaining hyperexcitability; second, loss of inhibitory transmitters and interneurons; and third, central sprouting of Aß-fibers after C-fiber atrophy. The long-term response is a reduction in threshold, which induces clinical phenomena, such as spontaneous shooting or electric shock-like pain sensations and stimulus-evoked hyperalgesia, allodynia, or both (2).

In many neuropathic pain states, interactions of the sympathetic nervous system with damaged sensory fibers and afferent neurons enhance the sensitized state as a framework for pain (3). The clinical consequence is a complex regional pain syndrome (CRPS).

CRPS I is often disproportionate to injury and not limited to a single nerve, whereas CRPS II follows nerve injury. Whereas patients with neuropathic pain suffer from hyperalgesia and allodynia, the CRPS diagnosis requires edema and sudomotor or motor abnormalities with sweating and skin dystrophy (4).

To establish a state of adequate analgesia, two approaches are possible: to mimic the body’s endogenous inhibitory system or to specifically interrupt nociceptive sensory transfer. The prime example of the first approach is the use of opiates, which act on opiate receptors with pharmacologically-controlled mode transition (5,6). Studies with morphine, fentanyl, oxycodone, and tramadol have demonstrated significant pain relief in patients with postherpetic neuralgia (7,8), peripheral neuropathic pain (9), diabetic neuropathy (10), and polyneuropathy (11), respectively. In these studies, the average number needed to treat to obtain one patient with 50% pain relief was 3.3; i.e., these drugs were effective in 30% of the patients (12).

The second approach is based on the use of sodium channel blockers—such as carbamazepine (CMZ)—that reduce rapid nociceptive input. Number-needed-to-treat values are around 2–3. Antidepressants as first-line drugs are equally effective. This means that in neuropathic pain, two to three patients have to be treated before one patient with 50% pain relief is obtained. Many physicians have reported limited success (13).

Despite the increasing number of trials in neuropathic pain, only the efficacy of antidepressants in diabetic neuropathy and postherpetic neuralgia has been proven. For anticonvulsants and opioids, experience is based on only few trials (12). Therefore, reliable clinical guidelines are not available (14).

Reasons for the limited number of studies are often patient related. Harmful side effects and the possibility of receiving a placebo or ineffective therapy under study conditions are deterrents. As a solution for this basic problem, a new study design was introduced. We studied patients with neuropathic pain whose neuronally perturbed transmitter and inhibitory systems could be restored by spinal cord stimulation (SCS) (15). After SCS inactivation, a sensitized state with lancinating or burning pain (A- and C-fiber mediated), dysesthesia or allodynia (Aß-fiber medi-ated), or both could be reproduced (16). This offered the possibility of developing an almost homogenous pain state to objectify the therapeutic effect of CMZ and morphine, because it can be achieved only in experimental models.

	Methods

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Seventy-seven patients with neuropathic pain were referred to our pain clinic during 1991–1996 because of inefficient pain medication and increasing pain. Careful analysis of the preceding therapy showed medications with weak opioids in 61%, strong opioids in 28%, and CMZ and antidepressants in 11%; these were taken up to 6 yr on an as-needed basis. These regimens may induce variable drug levels that are responsible for the patients’ insufficient pain relief. Many of these patients were reluctant to adopt a systematic time-contingent medication schedule, fearing that this would be ineffective. Therefore, test periods of SCS were performed. Sixty-eight patients (88%) preferred the final implantation of SCS devices, which resulted in permanent pain relief without any pain medication.

These patients were able to switch into a sensitized state by inactivating their SCS so that the influence of CMZ and morphine could be studied. In cases of intolerable pain, the reactivation of SCS was allowed. Under these "relaxed conditions," it was possible to recruit 43 patients with average treatment periods of 12.9 mo to participate in our trial ( Table 1).

The underlying diseases were isolated radiculitis after multiple disk operations at level L4-L5 in 17 patients, postherpetic thoracic neuralgia in 6, phantom limb pain in 3, diabetic neuropathy in 3, and peripheral nerve lesion as well as reflex sympathetic dystrophy (CRPS I) in 7 patients each. All patients were supplied with Medtronic ITREL II or III devices (Medtronic, Minneapolis, MN) (impulse amplitude 1–6 V, pulse width 50–200 ms, frequency 50–100 Hz).

Patients with signs of strong psychological and affective components in the Minnesota Multiphasic Personality Inventory and in an interview by psychiatrists were excluded from previous SCS treatment. The diagnosis was confirmed by neurologists.

The pain intensity was rated on a numeric analog scale (NAS) ranging between 0 and 10 points and documented every 2 h in the patients’ diaries. Drug-related adverse reactions, such as constipation, fatigue, sweating, headache, nausea, vomiting, dizziness, and ataxia, were also recorded.

Clinical examination, laboratory screening, and 12-channel electrocardiograms were obligatory. An initial switch-off test of the SCS system was performed, and only those who reported pain were included. Ninety-five percent of the patients reactivated their SCS within a period from 21 to 425 min (median 145 min) at a median pain level of 7 NAS, which means that spontaneous remission was not detectable (Table 1). This time range was considered representative for the generation of pain and accepted as a marker of spontaneous pain onset. Patients with arrhythmia, angina pectoris, or a history of allergy or cardiopulmonary insufficiency, as well as those using analgesics, were excluded.

The randomized study was designed as double blinded and placebo controlled in two phases. A drug adjustment period under SCS preceded the SCS-free test period.

In Phase 1, 43 patients were asked to stay at home for a 5-day dose adjustment period during SCS. The patients were randomly allocated to receive either 600 mg of CMZ (Tegretal®, 2 tablets each of 100 mg, 3 times daily; Novartis Pharma, Nurenberg, Germany) (n = 22) or placebo (2 tablets, 3 times daily) (n = 21). Plasma concentrations of CMZ had not been determined. Adjuvant therapies were resigned to avoid pharmacological interactions. In case of adverse effects, a dosage reduction was applied.

On the sixth day, all patients were clinically controlled, and the SCS was switched off. In cases of adequate analgesia, the patients continued the CMZ medication for 8 days. These patients and those who reactivated SCS early started a drug elimination period of 7 days, terminating Phase 1 to enter Phase 2. Patients who preferred to stay on CMZ did not enter Phase 2.

The patients who finished Phase 1 were admitted to the hospital for 2 days to control any risk of respiratory depression after opioids and were randomly allocated to receive either 90 mg of sustained-release morphine (Capros®, 1 tablet of 30 mg, 3 times daily; Medac, Hamburg, Germany) or placebo (1 tablet, 3 times daily). After the in-hospital dose-adjustment period, SCS was switched off. In cases of adequate analgesia, the patients continued the morphine medication for 8 days or longer, if preferred. Otherwise they reactivated their SCS. At the end of a 37-day follow-up, all patients had a final clinical examination.

The objective of the trial was to determine whether one of the test drugs was superior to placebo. The evidence should have had a statistical significance level of 5% and a power of >90%. According to this assumption, and with an expected difference in pain level of more than 5 NAS, a sample size of at least 8 patients was defined.

For the statistical analysis, the differences in pain onset and intensity were analyzed by the Wilcoxon test. The initial switch-off test was used to classify the patients’ responses. Patients under successful medication who quit SCS permanently were "responders." Patients who reactivated their SCS within the 95% range of the switch-off time were "nonresponders." Those who could overcome the upper limit of 425 min were "partial responders."

	Results

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Phase 1: CMZ Versus Placebo
The dose adjustment was unproblematic. In four and five cases, a dose reduction from 600 to 400 mg/d of CMZ and from 6 to 4 tablets per day of placebo was ordered in relation to the severity of adverse reactions, respectively. There was no significant difference in patients’ body weights between responders and nonresponders ( Tables 2, 3). The median dosages were nearly constant at about 7.5 mg · kg^–1 · d^–1 or 0.08 tablets per kilogram per day ( Fig. 1).

View larger version (38K): [in this window] [in a new window]   Figure 1. A, Frequency of side effects during Phase 1. B, Body weight-related dosage during Phase 1 (median and interquartile range).

After SCS inactivation, signs of A-, C- and Aß-fiber-mediated symptoms such as lancinating, burning, allodynia, or all three occurred in both groups proportionally (Tables 2, 3). Two patients achieved a state of analgesia comparable to that of SCS during a dosage of 600 mg/d of CMZ (responder) ( Fig. 2A). The pain increase in the remaining patients was considerably delayed. Twelve patients of the CMZ group accepted a pain increase up to 5.9 ± 2.1 NAS for 89 h, whereas 16 of the placebo group tolerated a maximum pain of 7.7 ± 1.6 NAS for only 45 h (partial responders) (Fig. 2B). These differences, with P_(NAS) = 0.04 and P_(t) = 0.03, respectively, were significant (Table 2).

View larger version (20K): [in this window] [in a new window]   Figure 2. Phase 1: The effect of carbamazepine (CMZ) and placebo (PL) on the pain level during the dose adjustment and test period. Spinal cord stimulation (SCS) was finished with the beginning of the test period. SCS was reactivated at the time of intolerable pain levels ( = SCS reactivation; *P < 0.05).

From the original 43 participants, 5 decided to leave the study, and 2 became CMZ responders. The remaining 36 agreed to attend Phase 2.

Phase 2: Sustained-Release Morphine Versus Placebo
In addition to these 36 patients mentioned above, 2 who interrupted Phase 1 early agreed to join Phase 2, so 38 patients could be randomly allocated to receive either morphine (n = 21) or placebo (n =17).

Because of nausea, dizziness, and vomiting, a dose reduction from 3 to 2 tablets once per day was ordered in eight patients of the morphine group ( Fig. 3). Nevertheless, the mean dosages could be stabilized between 1 and 1.25 mg · kg^–1 · day^–1 during the whole phase (Fig. 3). The frequency of adverse reactions was about 20 events per day in the morphine versus 2 in the placebo group. One patient of the morphine and two of the placebo group interrupted the trial early. After SCS inactivation, lancinating and burning pain, allodynic symptoms, or both were reported equally in both groups (Tables 2, 3).

View larger version (29K): [in this window] [in a new window]   Figure 3. A, Frequency of side effects during Phase 2. B, Body weight-related dosage during Phase 2 (median and interquartile range).

View larger version (20K): [in this window] [in a new window]   Figure 4. Phase 2: The effect of sustained-release morphine (MO) and placebo (PL) on the pain level during the dose adjustment and test period. Spinal cord stimulation was finished with the beginning of the test period. SCS was reactivated at the time of intolerable pain levels ( = SCS reactivation; *P < 0.05).

	Discussion

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Although our patients reflect a variety of diverse etiologies, the uniform reaction on SCS proves that the underlying mechanisms are probably the same. Immediately after SCS inactivation, the affected dorsal horn neurons switch into a painful "facilitated state" within 145 minutes (Table 1) (16). Because of the preceding drug adjustment, the development of the" facilitated state" with neuropathic pain symptoms could be observed under steady-state conditions. In contrast to clinical approaches, in which existing chronic pain states are reduced by drug titration until pain relief, we objectified the delay in pain generation. This unique mode offers the opportunity to determine the pain-relieving effect of CMZ and morphine. Because no significant interindividual body weight variations were evident (Tables 2, 3), the use of equivalent drug dosages seemed to be justifiable in all patients.

CMZ is the drug of choice in trigeminal neuralgia, but not in other peripheral neuropathic pain states (12,19). In fact, the recent discovery of sodium channels expressed on nociceptor neurons after nerve injury (20) offers new possibilities: CMZ as a sodium channel blocker can interrupt the continuing sensory transfer in sensitized neurons (21,22), especially when conditions of rapid neural firing occur.

The ability of CMZ to interfere with GABAergic and somatostatinergic mechanisms enhances its antinociceptive effects, as well as other less well studied mechanisms, including those that exert a blockade of calcium channels and excitatory amino acids (23).

With a daily dose up to 600 mg, a CMZ steady state could be expected in all patients during the adjustment period, which represents a range of 3–4 times that of the half-life of about 30 h (24,25) (Fig. 1). Because the incidence of nausea, dizziness, and ataxia reported by most of the patients correlates quite well with CMZ plasma level of at least 10 µg/mL and pain relief is reached within a range of 3–14 µg/mL (25,26), the observed side effects can be considered as an indicator of sufficient analgesia. Only in isolated cases with severe side effects did a dosage reduction become necessary.

Indeed, 2 responders and 12 partial responders confirmed the analgesic effect of CMZ. With a total of 63%, the success in patients with different peripheral neuropathic pain states is strikingly high and correlates with those results published recently (12). One responder was suffering from CRPS I, and the other had peripheral nerve lesions. Both became permanent responders with a mean pain level of 2.5 NAS on 600 mg/d of CMZ. The partial responders—concerning 50% lancinating, 30% burning, and 20% allodynic symptoms—demonstrated a significant delay in pain regeneration (Tables 2, 3), so it might be a matter of CMZ dosage to reach the same pain-relieving effects achieved by SCS. But this approach could not be realized because of the expected side effects of CMZ and diminished patients’ compliance.

Moreover, this study proves that CMZ induces analgesia in all types of peripheral neuropathic pain. However, opioids normally attenuate A- and C-fiber-mediated nociception via hyperpolarization of neurons and terminal leadings (6). Still, peripheral neuropathic pain itself can reduce opioid sensitivity, which is probably related to loss or lack of presynaptic opioid receptors (2), as well as the inability of opioids to overcome the increased activity in sensitized dorsal horn neurons (27).

This trial seems to confirm these possibilities. Although a pharmacological equilibrium could be expected within 24 hours in all the patients (5), only one demonstrated sufficient analgesia to morphine in a dosage of 90 mg/d for 13 days (Fig. 4; Table 3). Thirteen patients tolerated a pain increase under a mean dosage of 1.1 mg/kg body weight only 10 hours longer than those of the placebo group.

Although we used nearly the same mean dosage of 83 mg/d morphine, which was effective in the one double-blinded placebo-controlled trial on patients with nonmalignant pain (28), only a tendency toward pain relief was obvious in this study. Larger opioid dosages could not be realized because of intolerable side effects in the majority of our patients.

Because of the large distribution of µ-receptors in the brainstem centers (29), the systemic use of opioids is limited because they mediate both analgesia and side effects (5).

Nevertheless, whereas 95% of the candidates did not tolerate a switch-off time over 425 minutes in the initial switch-off test, 16 placebo patients in Phase 1 and 11 in Phase 2 accepted increasing pain for more than 44 hours under the study conditions (Tables 2, 3). This was six times longer than that during the initial switch-off test (Table 1). The magnitude and duration of pain increase were almost identical, although the patients were randomized twice and the structure of the groups differed.

The reproducibility of these results emphasizes the objectivity of our patients in the assessment of the drug actions. Therefore, the following conclusions may be drawn. The efficacy of CMZ in neuropathic pain was significant. However, the dose should be increased to a level of more than 600 mg/d for an adequate analgesia. Furthermore, sustained-release morphine in doses between 60 and 90 mg/d did not achieve significant pain relief. Larger dosages may be necessary, but these should be proven and weighed against increasing side effects in further investigations. SCS may be an alternative to pharmacological treatments in nonresponders, provided they accept an invasive approach.

	Acknowledgments

 
The authors would like to thank Mrs. B. Illgen, Director of Pharmacy, Klinikum Krefeld, for blinding the drugs and the participating patients for their goodwill and tolerance.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999