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Spinal Cord Stimulation in Postherpetic Neuralgia and in Acute Herpes Zoster Pain

Harke, Henning, MD; Gretenkort, Peter, MD; Ulrich Ladleif, Hans, MD; Koester, Peter, MD; Rahman, Salah, MD

doi: 10.1097/00000539-200203000-00040
Pain Medicine: Research Report

We studied the effects of spinal cord stimulation (SCS) on postherpetic neuralgia (PHN). Data of 28 patients were prospectively investigated over a median period of 29 (quartiles 9–39) mo. In addition, four patients with acute herpes zoster (HZ) pain were studied simultaneously. After intractable pain for more than 2 yr, long-term pain relief was achieved in 23 (82%) PHN patients (median, 70 yr) during SCS treatment confirmed by a median decrease from 9 to 1 on the visual analog scale (P < 0.001). In five cases with serious comorbidity, the initial pain alleviation could not be stabilized. Spontaneous improvement was always confirmed or excluded by SCS inactivation tests at quarterly intervals. Eight patients discontinued SCS permanently because of complete pain relief after stimulation periods of 3–66 mo, whereas 2 reestablished SCS because of recrudescence after 2 and 6 mo. Considerable impairments in everyday life, objectified by the pain disability index, were also significantly improved (P < 0.001). In 4 patients with acute HZ pain, SCS was promptly effective and after periods of 2.5 (quartiles 2–3) months the pain had subsided. SCS seems to offer a therapeutic option for pharmacological nonresponders.

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

October 24, 2001.

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

Postherpetic neuralgia (PHN) is a neuropathic pain syndrome that is often intractable. PHN is defined as pain persisting for more than 6 mo after rash healing of acute herpes zoster (HZ) (1). In contrast, for many individuals, HZ is a short-lived disorder with unbearable pain as well.

The most important data for evaluating the risk of PHN are provided by a meta-analysis of 14 placebo-controlled trials of acyclovir (2), which showed that 22% of placebo-treated patients had pain persisting at least for 3 mo. PHN is infrequent in patients under 40 yr, but 70% of patients over 60 yr, report pain at 1 mo after rash healing. The proportion of patients with pain at 1 yr approaches 50% in those over 70 yr (3,4).

The etiology of pain is well known: the recrudescence of dormant varicella-zoster virus, which typically occurs in elderly immunodeficient individuals (1,5), initiates an inflammation of sensory ganglia and peripheral nerves, inducing abnormal nociceptor sensitization and central hyperexcitability (6). In some patients, pain persists for months, years, or indefinitely after healing of the shingles lesions (1,4).

Patients with PHN report constant burning, throbbing or arching pain, intermittent sharp, shooting pain and mostly tactile allodynia. These symptoms may be explained by three distinct pathophysiological mechanisms: first, constant drive of input from abnormally hyperactive (irritable), anatomically intact primary afferent nociceptors results in central sensitization with marked allodynia but minimal sensory loss (6–8); second, loss of C-nociceptors and fibers initiate central sprouting of Aβ-fibers, contacting the receptors formerly occupied by C-fibers, and leads to hyperalgesia and allodynia (6,9); and third, loss of both large and small diameter fibers generates spontaneous activity in deafferented central neurons producing constant pain in a region of profound sensory deficits without allodynia, i.e., anesthesia dolorosa (6).

These different mechanisms may coexist in individual patients. Therefore, pharmacological treatment often has limited success. The calculated number needed to treat was 2.3 for tricyclics, 3.2 for gabapentin, 2.5 for oxycodone, and 5.9 for capsaicin (10,11). This means, that, compared with placebo, 2 to 6 patients have to be treated before 1 patient with a pain relief of >50% is obtained. There is evidence, however, that a significant proportion of patients does not receive adequate pain management. The main reasons for failure of treatment are as follows: first, potential ineffectiveness and risks of pharmacotherapy (11); second, intolerable side effects like dizziness, nausea, and vomiting, which often prevent required inhibitory concentrations in the central nervous system (CNS) (12) and result in negative attitudes toward such treatments; and third, the comorbidity in the elderly, especially of the cardiovascular system and CNS (13).

These disadvantages of systemic pharmacotherapy may be avoided by electrical stimulation of the posterior spinal cord, activating supraspinal and spinal inhibitory pain mechanisms (14). Spinal cord stimulation (SCS) may reestablish the impaired balance between excitatory and inhibitory mechanisms in sensitized dorsal horn neurons (15) as long as intraspinal neuronal death or complete deafferentation does not result from PHN (16). In the present trial, the efficacy of SCS was investigated in PHN and HZ patients with preserved sensory function refractory to conventional pharmacotherapy.

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In accordance with the declaration of Helsinki, the objectives of the study were explained, and all patients gave their informed consent. The study was approved by the ethical committee of the medical association of Nordrhein, Düsseldorf, Germany.

Twenty-eight consecutive patients with PHN and four with acute HZ pain, referred to our pain clinic during 1994–2000 because of ineffective pain medication and increasing pain, were enrolled in the study.

Twenty-five patients reported pain in the thoracic segments (the predominant localization), five in the cervical and two in the lumbar dermatomes. Sensory function was rated by focal tactile stimulation as usual and dynamic mechanical allodynia was determined with a foam paintbrush by stroking from normal skin toward the painful area. The patients had no or little sensory loss in the affected dermatomes. The quality of pain was reported as burning, intermittent lancinating or shooting pain and allodynia irrespective of patients’ antiviral medication. Most of the patients (57%) had not received any antiviral therapy. The diagnosis of PHN was confirmed by neurologists.

With few exceptions, all patients suffered from cardiovascular, brain, lung, or endocrine disorders or cancer, respectively. The baseline characteristics of the 32 patients are summarized in Table 1.

Table 1

Table 1

Careful analysis of preceeding therapy in PHN showed medications with weak opioids in 12, strong opioids in 7, antidepressants in 6, anticonvulsants in 5, peripheral analgesics in 6, and corticosteroids in 2 cases. The medications were taken up to 2 yr (quartiles 12–60 mo) on an as-needed basis; such a regimen may induce variable drug levels that may be responsible for the insufficient pain relief. Many of these patients were reluctant to adopt a systematic time–contingent medication schedule, fearing that this would be ineffective, and therefore preferred an invasive approach. This approach was also applied to four acute HZ patients with intractable pain treated by strong opioids (10 mg of sustained release morphine 3 times daily) without any pain relief. At first, oral medications were continued.

All patients underwent identical pain and sensory assessment in quarterly intervals. The overall pain intensity was assessed by the patients in a diary 4 times a day, using a visual analog scale (VAS) ranging between 0 and 10 points (0 = no pain, 10 = unbearable pain). The median VAS was calculated and registered quarterly at the time of the follow-up examinations.

Patients’ impairment in everyday life was rated at baseline and at the end of every quarter by the pain disability index (PDI), using scores between 0 and 10 (0 = no disability, 10 = total disability) to objectify the interfering influences on home responsibilities, recreation, social activities, occupation, self-care, and sexual behavior, as well as life support activity (17). Furthermore, the consumption of analgesics, antidepressants, anticonvulsants as well as steroids was recorded in the patients’ diary.

As a primary prerequisite for eligibility to SCS treatment, we examined the patients’ response to selective sympathetic nerve blocks and assessed the psychological profile according to the Minnesota Multiphasic Personality Inventory (MMPI) (18) with respect to hypochondriasis and hysteria to exclude patients with strong neurotic disorders (19,20).

The implantation of the SCS devices in the PHN patients was performed in a two-stage procedure. The first one involved the percutaneous placement of a quadripolar lead into the epidural space, where paresthesias topographically related to the affected region were elicited with alternating electrical fields between the four electrode contacts. After optimal “paresthesia coverage” of the affected dermatomes and final positioning, we preferred to secure the lead surgically by anchoring it to the supraspinous ligament and exteriorizing the system to a temporary transmitter (Medtronic Screener 3625; Medtronic Minneapolis, MN) for a 5–7 day trial stimulation period.

After successful trial stimulation, the second stage required connecting the extension lead to the pulse generator, pocketed subcutaneously in the abdominal wall. All patients were supplied with Medtronic ITREL II or III devices (Medtronic, Minneapolis, MN) for continuing stimulation.

In patients with acute HZ pain, a bipolar lead was inserted percutaneously, anchored to the skin and attached to an external temporary transmitter system (Medtronic Screener 3625). According to patients’ response, the following stimulation ranges were used: pulse width 90–450 ms, frequency 50–130 Hz, current 1–6 V.

To assess the efficacy of treatment, SCS inactivation tests were performed, i.e., the stimulation was turned off until the pain reappeared. This modality was repeated quarterly to objectify the existence of pain-free intervals or spontaneous improvement with complete pain cessation. The results were determined and documented in the study protocol. In cases of sufficient pain relief, analgesics were ceased.

A long-term follow-up with a quarterly examination was conducted to control the whole neuromodulation system and to ensure the accurate placement of the leads.

For statistical analysis, differences in pain intensity and in psychometric scales were analyzed by the paired-samples Wilcoxon’s test. Differences in drug therapy were analyzed by χ2 test.

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PHN Patients

Twenty-eight patients had a history of severe pain with a median level of 9.0 (quartiles 7.75–10) VAS for 24 (quartiles 12–60) months (Table 1). All patients responded to selective sympathetic nerve blocks and did not show marked increases on hypochondriasis and hysteria scales in the MMPI. Immediately after the beginning of the SCS treatment, satisfactory paresthesia “coverage” of the entire painful dermatomes was achieved, so that the initial overall pain intensity could be significantly reduced in allpatients from 9 to 1 VAS in average during the test period (Table 2, Fig. 1). No patient discontinued the trial and all received permanent devices.

Table 2

Table 2

Figure 1

Figure 1

A long-term pain relief was observed in 23 patients (long-term responders). These patients reported a median pain level of 1.0 VAS (quartiles 1.0–2.75) for burning and lancinating pain as well as allodynia even after a median follow–up period of 29 (quartiles 9–38.5) months (Table 2, Fig. 1A).

Fifteen of the 23 patients are still using SCS today. Spontaneous improvement was repeatedly excluded by reoccurrence of pain at quarterly SCS inactivation tests: a painful state of 7 VAS (quartiles 6–8) was acquired within a median period of 4 (quartiles 1–46) h. After SCS inactivation tests, two of these patients (WH, KJ) reestablished SCS after a stimulation-free interval of 2 and 6 mo, respectively, because of gradually worsening pain.

Nonetheless, the remaining 8 patients discontinued SCS permanently because of low pain levels or spontaneous improvement after stimulation periods of 3–66 mo. These patients were subsequently pain-free for 10 (quartiles 3– 23) mo, and the SCS devices were explanted in two cases (Table 2).

Finally, five patients became progressively demented and were unable to comply with SCS therapy (short-term responder). After successful response for an average of 8 mo, the median pain level increased from 1 to 7 VAS (Fig. 1B, Table 2). A valid assessment of pain intensity was not possible in further follow-up examinations: three of these patients rated high VAS values and, nevertheless, did not want to resign their SCS devices. In two of these cases, SCS was explanted.

In the 23 long-term responders, impairments and functional limitations in everyday life of more than 40%–80% were significantly improved during the SCS treatment, indicated by normal PDI scores (P < 0.001) (Fig. 2). Furthermore, preexisting pain medications could be completely removed or significantly reduced: Only one continuing prescription of an initial 19 opioid analgesic prescriptions was necessary along with SCS (P = 0.002). Peripheral analgesics, corticosteroids and anticonvulsants were reduced similarly (P = 0.05). All in all, 13 of the 23 long-term responders did not require any pain medication during SCS therapy (P = 0.02). However, because of depressive symptoms, antidepressants were the appropriate comedication in 14 cases (P < 0.05) (Fig. 3). An analgesic effect of antidepressants could not be objectified because all patients experienced reappearance of pain during the inactivation test after a poststimulatory pain suppression lasting more than 0.5–1 h (Table 2).

Figure 2

Figure 2

Figure 3

Figure 3

The generator unit had to be exchanged in nine patients because of flat batteries after 2 yr of continuous stimulation. In three cases, the paresthesia coverage of the painful dermatomes was varying so that the single-lead systems had to be replaced surgically with good result.

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Acute HZ Patients

Four patients had unbearable acute HZ pain for a median period of 1.8 mo (Table 1). The patients received temporary percutaneous bipolar SCS systems and reported immediate pain relief. The initial median pain intensity of 9 VAS could be promptly reduced to 1.0 VAS. The stimulation could be terminated after a median period of 2.5 (quartiles 2.0–3.1) mo because of complete pain cessation (Table 2). All patients had normal PDI scores, no functional impairment, and a normal rash healing. The patients remained without complaints for 13–39 mo (Table 2).

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A major finding of this study is the favorable long-term outcome of SCS treatment. Eighty-two percent of the patients experienced long-term pain relief after a mean follow-up period of 29 months. A literature review, however, showed that the response of PHN to SCS was less predictable: Success rates of 27% to 60% were reported (21–24). Considering these different results, it is important to realize that the progression of disease or spontaneous improvement is a genuine disease-related phenomenon that may reflect its variable history (25). There are patients with pain as well as allodynia resulting from sensitized irritable nociceptors maintaining central sensitization, which applied to our patients. These subjects with preserved neuronal and dorsal column function responded well to SCS. However, there are patients with marked sensory loss in the affected dermatomes and in constant pain without allodynia, i.e., anesthesia dolorosa (6). To the extent that deafferentation and degeneration of dorsal column fibers are the dominant mechanism, patients would experience no change in pain with SCS (16).

SCS effects are necessarily dependent on anatomically intact pathways: the antidromic activation of dorsal column and root fibers may induce two dominant mechanisms: first, a pre- and postsynaptic inhibition of the afferent barrage from injured peripheral neurons via GABA-ergic interneurons (14); second, suppression of sympathetic overdrive, already mentioned in PHN (26).

Microdialysis studies, using mononeuropathic rat models, have demonstrated that the release of γ-aminobutyric acid (GABA) and the activation of the GABA-B and adenosine A-1 receptors by SCS, may actually inhibit the release of the excitatory amino acids glutamate and aspartate in the dorsal horn, thus suppressing neuronal pain transmission and sympathetic outflow (14,27). Because hyperexcitability and allodynia in neuropathic pain seems to be related to dysfunction of the spinal GABA systems, the impaired balance between excitatory and inhibitory mechanisms may be reestablished by SCS, resulting in a “nearly normal painless state“ of previously facilitated neurons.

Twenty-three of the 28 subjects (82%) were classified as SCS long-term responders based on almost complete pain relief under continuing stimulation. The progression or spontaneous improvement of PHN was objectified by the SCS inactivation test at quarterly intervals. After a period of pain suppression, lasting at least 0.5–1 h, all patients experienced a reappearance of pain during the test, confirming that continuing pain relief was associated with SCS.

However, after SCS treatment periods of 3 to 66 months, permanent pain relief was achieved in 8 patients even during the inactivation tests. This may be attributed to the variable history of PHN with the probability of spontaneous pain resolution. Epidemiological data confirm that 54% of PHN patients with good outcome had been without any pain therapy (25). This possibility has to be considered even though an augmentation of microcirculation probably induced by inhibition of sympathetically controlled α1 receptors may explain a curative effect of SCS (14,27).

Five patients responded to SCS during the initial phase only. These were characterized as short-term responders because progressive dementia led to unrealistic and confused statements without any therapeutic chance.

A major aspect for successful SCS outcome is the achievement of an ideal distribution of paresthesia covering the painful area and affected neuronal structures. In our experience, paresthesia coverage in PHN represents a difficult problem as pain in patients’ perception may expand into surrounding unaffected regions (6,8). SCS trials have reported the use of wire electrodes inserted percutaneously under local anesthesia as well as surgical implantation of plate electrodes under general anesthesia (21–24). However, one of the main drawbacks of the latter approach is that verbal communication with the patient for optimal paresthesia coverage with exact placement of the lead is impossible.

Regarding the SCS techniques, different electrodes, frequencies, pulse widths, and amplitudes were tried. Shimoji et al. (21) preferred low-frequency (1.6–8 Hz) and short period stimulation, whereas Simpson (22) and Meglio et al. (23) were successful with frequencies of 50–120 Hz and continuous stimulation. However, our patients reported optimal pain relief on using continuous high frequencies with moderate intensity necessary for stimulation of both the sensory and sympathetic pathways (14).

Although the role of the sympathetic nervous system in the development and maintenance of PHN is uncertain (28), there is evidence to link sympathetic activity and pain. A positive response to sympathetic local anesthetic blocks provides short-term pain relief in PHN (26). However, long-term effects of sympathetic maintained pain in PHN could be achieved by high intensity SCS with a marked inhibition of the efferent sympathetic activity (14,27,29).

Considering the pathophysiological disorders in PHN and HZ, SCS may offer the possibility for a new, “two-track“ intervention: first, normalizing the neuronally perturbed transmitter and inhibitory system, and second, attenuating the sympathetic activities in dorsal horn and dorsal root ganglion neurons.

For our trial, optimized conditions could be realized via the following measures: first, placement of the lead with exact paresthesia coverage under verbal communication, controlled in quarterly intervals; second, immediate surgical revisions after lead migration in three cases reproducing optimal response; third, the ability of our patients to rate and describe their pain relief precisely without conspicuous emotional components confirmed by normal MMPI profiles. This comprehensive strategy may explain why more than 80% of our patients experienced sufficient pain reduction.

In the present trial, SCS offered a convenient pain management for PHN and HZ patients. The highly impaired psychosocial, self-care and life support activities were frequently reestablished to a high degree. The SCS treatment is also associated with a decreased consumption of drugs, supporting this favorable approach.

Although the results of the present trial do not meet the requirements of a high level of evidence, we can conclude that SCS treatment of PHN may offer a worthwhile option in the treatment of pharmacological nonresponders with anatomically intact neural pathways, provided the patients accept an invasive approach. In cases of unbearable HZ pain, this approach may have supportive benefit as well.

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