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Deep Brain Stimulation for the Control of Pain
Epilepsy & Behavior 2, S55–S60 (2001) doi:10.1006/ebeh.2001.0206, available online at http://www.idealibrary.com on
Deep Brain Stimulation for the Control of Pain Ira Garonzik, M.D., Amer Samdani, M.D., Shingi Ohara, M.D., and Frederick A. Lenz, M.D., Ph.D. 1 Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, Maryland 21287 Received May 11, 2001; accepted for publication May 14, 2001
The most common sites of deep brain stimulation (DBS) for relief of pain are the periaqueductal gray (PAG) for nociceptive pain and the principal sensory nucleus of the thalamus (Vc) for control of neuropathic pain. The mechanism of action of PAG stimulation seems to involve release of endogenous opiates, whereas the mechanism of Vc stimulation may involve either antidromic activation of the spinothalamic tract or orthodromic activation of thalamocortical relay cells. Success rates are higher for PAG stimulation than for Vc stimulation, but long-term success rates for both are in the range 40 to 60%. The rate of complications with DBS is lower in recent literature of DBS for movement disorders than in earlier literature of DBS for pain, suggesting that hardware modifications have decreased the rate of complications. DBS is an option in patients with chronic pain who are refractory to other modes of medical and surgical therapy. © 2001 Academic Press Key Words: pain; deep brain stimulation; thalamus; periaqueductal gray.
review is restricted to somatogenic as opposed to psychogenic pain (7). Somatogenic pain is classified into nociceptive and neuropathic pain. Nociceptive refers to pain arising from the activation of peripheral nociceptors and transmitted to the central nervous system through intact somatosensory pain pathways. Examples of nociceptive pain include pain of acute trauma and cancer pain secondary to invasion of bone. This pain responds well to opiates. Neuropathic pain refers to pain arising from injury to the nervous system either peripherally (deafferentation pain, e.g., diabetic neuropathy) or centrally (central pain, e.g., poststroke pain) (7). It has been proposed that this type of pain does not respond to opiates (8), although further study of this proposal may be required (9, 10).
Electrical stimulation of subcortical structures in the brain (deep brain stimulation, DBS) for pain control was first reported in the 1950s when hypothalamic nuclei were stimulated for treatment of chronic pain (1, 2). The relief of pain with chronic electrical stimulation of sensory thalamic nuclei was first reported by Mazars et al. (3). A few years later mesencephalic stimulation-evoked analgesia was reported in chronic pain patients (4, 5). During the ensuing decades, the sensory thalamus and periaqueductal gray (PAG) became the most frequent targets for stimulation. These initial surgeries were based on studies in animals. Since that time, potential mechanisms for stimulationevoked analgesia have been proposed, based partly on the clinical results of retrospective studies of stimulation-evoked analgesia in humans (4, 5). The International Association for the Study of Pain’s Classification of Pain defines pain as an unpleasant sensory or emotional experience associated with actual or potential tissue damage or that which is described in terms of such damage (6). Chronic pain is pain that occurs daily over a 6-month period (6). This
DBS FOR PAIN RELIEF: MECHANISMS OF ACTION In 1969, Reynolds demonstrated that focal stimulation at the lateral margin of the PAG in rats prevented nociceptive responses during abdominal surgery without concomitant drug administration (11). These results were confirmed by Mayer and co-workers (12). Subsequently these effects were reported to be reversible with the administration of opioid antagonists (4).
1
To whom correspondence should be addressed at Department of Neurosurgery, Meyer Building 7-113, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287-7713. Fax: (410) 6149877. E-mail: [email protected]. 1525-5050/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
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S56 Endogenous opioids were elevated in the third ventricle after PAG stimulation (13, 14) although the mechanism of this effect might not be due to release of opioids by stimulation (15). Analgesia produced by stimulation of PAG occurs in the absence of other motor, sensory, or cognitive effects (4, 5). Several lines of evidence suggest that the mechanism of this analgesia involves a spinal connection (16, 17). First, while the PAG neurons rarely project directly to the spinal cord, they do project monosynaptically to the medullary nucleus raphe magnus (NRM). In turn, the NRM sends a strong serotonergic projection to the dorsal horn. Second, the analgesic effect of PAG stimulation is abolished by cutting descending pathways to the spinal cord. The PAG, medullary NRM, and dorsal horn all contain high levels of opiates and opiate receptors, suggesting that these structures mediate opiate-induced analgesia. In humans, infusion of opiates into the intraventricular or spinal subarachoid space causes analgesia (18). These results suggest that PAG stimulation evokes analgesia by activation of the medullary NRM, which sends a serotonergic projection to the dorsal horn. Opiates may be involved in the mesencephalic and spinal components of this pathway. The mechanism by which thalamic somatosensory stimulation provides pain relief is not fully understood. The target nucleus for this type of stimulation is the principal somatosensory nucleus known as ventral caudal (Vc) in humans and ventral posterior (VP) in other species, including monkeys (19) and rats. Benabid and co-workers found that stimulation of the VP of the rat inhibited responses to noxious stimuli of cells in a thalamic intralaminar nucleus (nucleus parafascicularis) through an opioid-independent mechanism (20). Furthermore, the inhibition did not appear to involve dorsal horn neurons of the spinal cord, because stimuli that inhibited nucleus parafascicularis neurons did not affect the responses of a limited sample of dorsal horn interneurons. Gerhart and co-workers demonstrated the inhibitory effect of thalamic stimulation on lamina I to V spinothalamic tract (STT) neurons (21). The mechanism of this effect was thought to involve either orthodromic or antidromic mechanisms. Thalamic stimulation might anterogradely activate cortex and hence produce STT cell inhibition through the corticospinal tract (21, 22). Alternatively, stimulation-evoked STT activation might antidromically activate collaterals to PAG, which projects to NRM or to the cells of origin of reticulospinal pathways (see above), or could antidromically activate collaterals to NRM. NRM has a serotonergic Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
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spinal projection that could inhibit STT cells (23). Alternatively, any of these descending systems could activate propriospinal systems or dorsal horn interneurons (21). Sorkin and co-workers have shown that electrical stimulation of the VPL nucleus elicited increases in extracellular serotonin concentration in the monkey spinal cord (24). They hypothesized that thalamic stimulation activated collaterals to the cells of origin of the NRM–spinal tract, which in turn released serotonin, a modulator of nociceptive transmission. Finally, abnormally increased rates of thalamic bursting are reported to occur in neuropathic pain states and might be related to the sensation of chronic pain (25, 26; cf. 27). Stimulation in Vc could block this activity and so relieve the pain. Thus a variety of mechanisms may explain the efficacy of Vc stimulation for the relief of pain.
PUBLISHED STUDIES OF DBS FOR PAIN Patient Selection and Surgical Technique Three large studies of DBS for the control of chronic pain have been recently published (28 –30). In all three studies, patients were selected for DBS if they experienced chronic pain unresponsive to medical or surgical therapies over many years and to treatment administered during an admission to a pain clinic. Additionally patients underwent a psychological assessment. Among these studies the most complete assessment included a Minnesota Multiphasic Personality Inventory (31) and interviews with the patient and his or her spouse (28). Patients were chosen for stimulation if there was no evidence of psychological issues or of “secondary gain or other maladaptive functional characteristics.” In the other studies, only selected patients underwent psychological assessment (29, 30). Patients judged free of significant psychopathology were subjected to a morphine test during which they blindly rated their chronic pain in response to intravenous administration of placebo and morphine sulfate (4). This test is based on the hypothesis that nociceptive but not neuropathic pain responds to opioids (9; cf. 8, 10). In one study, reversibility of analgesia with naloxone was taken as an additional indicator that the analgesia was opiate-mediated (28). If the morphine test dose produced a major change in pain ratings, then the patient was assumed to have noci-
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ceptive pain and was selected for PAG stimulation. If there was no major change in pain ratings and the patient had a neuropathic clinical picture, then the patient was assumed to have neuropathic pain without a major nociceptive component and was selected for thalamic stimulation. In one of these studies, some patients without a major change in pain ratings were thought to be tolerant of the opioid-mediated effect of such stimulation (30). There was some evidence to suggest that l-tryptophan administration may reverse this presumed tolerance to stimulation (32). Therefore all patients without a major change in pain ratings in response to morphine were given oral l-tryptophan over a 4-week period in an attempt to reverse the presumed opioid tolerance (30). The morphine test was then repeated and patients who experienced a major change in pain ratings at that time had electrodes implanted in PAG. Surgical targets for PAG were determined by different means in the three studies. All targets were determined relative to the anterior commissure–posterior commissure (AC–PC) line, a third ventricular radiologic landmark with a relatively fixed anatomic relationship to subcortical structures (33). Levy and coworkers targeted a point 1 mm below and 1 mm posterior to the posterior commissure and 3 mm lateral to the lateral wall of the third ventricle (29). Young and Rinaldi targeted a point 2 to 3 mm below the AC–PC line and 12 to 14 mm posterior to the midpoint (MC) of the AC–PC line and 2 to 3 mm lateral to the midline (28). Hosobuchi targeted a site at the level of the opening of the aqueduct into the third ventricle and 3 mm lateral to the midline (30). The correct target was identified by stimulation-evoked warmth, oscillopsia, loss of up-gaze, elevation of both heart rate and blood pressure, or pain relief (28 –30). If the electrode is implanted more ventrally and posteriorly, fear and anxiety are evoked by stimulation (30). Periventricular gray, which is slightly rostral to PAG, has been targeted as an alternative site to PAG in some studies. The periventricular gray is located 10 mm posterior to MC and at the vertical level of the AC–PC line and 3 to 4 mm lateral to the midline (28). Levy and co-workers described sites of thalamic targets for treatment of deafferentation pain (29). Targets for facial deafferentation pain in the Vc medial (facial representation of Vc) were chosen 8 mm posteriorly to the MC point, 8 mm lateral to the midline, and 1 to 3 mm above the MC point (29). Deafferentation pain of the extremities was treated by stimulation of Vc lateral (representation of the extremities) defined as a point 9 mm posterior to MC, 10 to 12 mm lateral,
and 2 to 3 mm above the MC point. Other studies (28, 30) stated that targets were calculated from standard atlas maps (33). All studies included a period of testing with the electrode attached to an externalized lead. Patients were stimulated at different electrode combinations, voltages, pulse widths, and frequencies until the optimal stimulation parameters for pain relief were determined (28 –30). The results of this period of postoperative testing were used to decide whether or not to implant the stimulator. However, none of these papers included their criteria for deciding to attach the electrode to a receiver or stimulator and implant the system. Results The study by Young et al. (28, 34) retrospectively reviewed 178 patients undergoing DBS for chronic pain over a 14-year period. Eighty percent of patients (n ⫽ 89) had permanent implantation of the system including the pulse generator and the lead. The remaining patients failed to obtain pain relief during the test stimulation period; therefore, the electrode was removed and no stimulator was placed. Young assessed pain relief based on the following three criteria: (a) patient’s subjective evaluation of pain relief (visual analog scale of intensity change of greater than 50% with stimulation (35)); (b) effect on patient’s narcotic usage; and (c) change in patient’s functional capacity (28). Of the 89 patients with a permanent implant, 62% experienced long-term relief of pain. According to this study, long-term relief was obtained among 70% of patients with nociceptive pain who had permanent implants as compared with 50% of patients with neuropathic pain who had permanent implants. Young and co-workers relied on screening tests such as response of pain to opiates and reversal of response with naloxone to determine electrode target location early in their experience with DBS for pain (34), but not later (28), when they implanted electrodes in both periventricular gray and Vc in most patients (28). The most effective combination of stimulation through these two electrode systems was determined during postoperative testing. They did not find oral tryptophan a useful agent against the development of tolerance to stimulation (28), in contrast to other reports (30). The second study reported the results of DBS for chronic pain in 141 patients who were followed for 80 months (29). These patients had a mean period of pain Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
S58 of 65 months before surgery. The patients were divided into two groups: deafferentation pain states (84 patients) and nociceptive pain states (51 patients). Although screening tests (morphine intravenous infusion and naloxone reversal) were not used consistently throughout the series, the combination of the morphine test with the patient’s clinical picture was used to determine the appropriate site of implantation (see Patient Selection and Surgical Technique). Patients with a positive response to the morphine test were considered candidates for PAG stimulation and those patients unresponsive to the morphine test and with the clinical picture of neuropathic pain were considered for thalamic stimulation. Patients with mixed clinical pictures had electrodes placed in both locations. Outcomes were measured at 6 weeks (initial) and then at a later date with a mean of more than 6 years (long-term). Success was measured by regular use of the stimulator for relief of pain. There was a 61% initial success rate and a 30% long-term success rate for patients with various forms of deafferentation pain (29). Patients with nociceptive pain states had a 56% initial success rate and a 32% long-term rate. Examination of the individual subgroups within the pain states revealed that the patients with anesthesia dolorosa and pain after spinal cord injury had very low long-term success rates (⬍20%), while those with peripheral neuropathies had a 50% long-term success rate. The third study, by Hosobuchi and co-workers, reviewed 122 cases of chronic pain treated with DBS (30). The follow-up period ranged from 2 to 14 years and the mean duration of chronic pain was 6.5 years. Stimulation was considered to be a success if pain was controlled and narcotics were discontinued. Functional capacity such as return to work was not used as a measure of outcome. The authors relied on screening tests to determine target location of the electrode. Ninety-six patients with deafferentation pain had stimulators placed in Vc and 52 (68%) had initial success while 44 (57%) had long-term success. Within the deafferentation group, patients with postcordotomy dysesthesia had the best long-term response, and patients with anesthesia dolorosa had the worst longterm outcome. Sixty-five patients with nociceptive pain had bilateral PAG implants and 50 patients (77%) reported long-term success. This group comprised predominantly patients with chronic back and leg pain secondary to degenerative disease of the lumbar spine and patients with cancer pain. Thirty-six patients had both thalamic and PAG stimulators placed. Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
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Of these 36 patients, 19 had chronic back and leg pain; the back pain responded better to thalamic stimulation and the leg pain responded better to PAG stimulation. Seventeen patients had central deafferentation pain that responded only to thalamic stimulation and not PAG stimulation.
Complications The most serious complication of this procedure is intracranial hemorrhage. In one series, hemorrhage occurred in 5 of 141 cases with 1 death; 2 patients were left with permanent neurologic deficits, and 2 patients had no sequelae (29). In another series, 3 ventricular and 2 intracerebral hemorrhages occurred among 122 patients (30). Two patients died of the hemorrhage. In the third study, 2 thalamic and 2 subdural hemorrhages were reported (28); none was fatal. The rate of intracranial hemorrhage was attributed to the rough outer profile of an older electrode (30). A lower rate of hemorrhage has been reported with introduction of a redesigned electrode widely used for treatment of tremor (36). Neurologic sequelae of stimulation occurred in 7% of cases (28), including eye movement disorders (diplopia, vertical gaze paresis, blurred vision, oscillopsia), hemineglect, and hemiparesis (28, 29). Transient hemior monoparesis, lethargy and confusion, and dysphasia not apparently related to stimulation were described in one study (29). Persistent headache occurred in 50% of cases in one series (29) but was not mentioned in the other series. Infections occurred in 5 to 12% of cases (28 –30). The majority of organisms were Staphylococcus species (29). Stitch and subgaleal infections were the most common infections (30). The use of antibiotics alone cured superficial infections (28) and hardware infections in three cases (28, 30). Removal of the system and treatment with antibiotics was successful in all cases in which this approach was tried (30). The most serious infectious complications were ventriculitis (Proprionobacterium) and subdural empyema (Staphylococcus aureus), each occurring in one patient (30). Technical problems were reported in all studies, including migration of the electrode (2–10%) and fracture of the insulation (3– 4%) (28 –30). Skin erosion of the connector between the electrode and the coupling lead was reported in 2% of cases (30). These complications were corrected by removal of the nonfunctional system or replacement of the system. The rate of these complications has decreased with the rede-
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signed electrode (36), although the length of follow-up with the newer lead is shorter.
3.
4.
SUMMARY 5.
A meta-analysis of 13 studies (1114 patients) evaluating DBS for the treatment of chronic pain has recently been reported (37). Fifty percent of patients had long-term successful pain relief overall. Of patients with nociceptive pain (n ⫽ 419), 60% had long-term success with DBS. Among these patients, 59% had long-term success with PAG stimulation whereas Vc stimulation was successful in none of the patients stimulated. Of patients with neuropathic pain (n ⫽ 644), 54% had long-term success with DBS overall. Among patients with neuropathic pain, the long-term success of Vc stimulation was 56% whereas PAG stimulation was successful in 23%. To summarize, DBS is carried out in the PAG for nociceptive pain and in the principal sensory nucleus, Vc, for control of neuropathic pain. Success rates are higher for PAG stimulation than for Vc stimulation, but long-term success rates for both are in the range 40 to 60%. Rates of complications and side effects in the early literature are high. These rates seem to be lower in the recent literature of DBS for movement disorders, suggesting that hardware modifications have been effective. Thus, these procedures are still an option in patients with chronic pain who are refractory to other modes of medical and surgical therapy. Finally, DBS has focused attention on the pain modulatory system and advanced our understanding of that system.
ACKNOWLEDGMENTS
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Mazars G, Merienne L, Ciolocca C. Intermittent analgesic thalamic stimulation: preliminary note [in French]. Rev Neurol (Paris) 1973;128:273–9. Hosobuchi Y, Adams JE, Linchitz R. Pain relief by electrical stimulation of the central gray matter in humans and its reversal by naloxone. Science 1977;197:183– 6. Richardson DE, Akil H. Pain reduction by electrical brain stimulation in man. Part I: Acute administration in periaqueductal and periventricular sites. J Neurosurg 1977;47:178 – 83. Turk DC, Okifuji A. Pain terms and taxonomies of pain. In: Loeser JD, editor. Bonica’s management of pain. Philadelphia: Lippincott/Williams & Wilkins, 2001:17–25. Portenoy RK. Mechanisms of clinical pain: observations and speculations. Neurol Clin 1989;7:205–30. Arner S, Meyerson BA. Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain. Pain 1988;33:11–23. Vecht CJ. Nociceptive nerve pain and neuropathic pain. Pain 1989;39:243– 6. Dellemijn P. Are opioids effective in relieving neuropathic pain? Pain 1999;80:453– 62. Reynolds DV. Surgery in the rat during electrical analgesia induced by focal brain stimulation. Science 1969;164:444 –5. Mayer DJ, Wolfle TL, Akil H, Carder B, Liebeskind JC. Analgesia from electrical stimulation in the brainstem of the rat. Science 1971;174:1351– 4. Akil H, Richardson DE, Hughes J, Barchas JD. Enkephalin-like material elevated in ventricular cerebrospinal fluid of pain patients after analgetic focal stimulation. Science 1978;201: 463–5. Hosobuchi Y, Rossier J, Bloom FE, Guillemin R. Stimulation of human periaqueductal gray for pain relief increases immunoreactive beta-endorphin in ventricular fluid. Science 1979;203: 279 – 81. Fessler RG, Brown FD, Rachlin JR, Mullan S. Elevated betaendorphin in cerebrospinal fluid after electrical brain stimulation: artifact of contrast infusion? Science 1984;224:1017–9. Basbaum AI, Fields HL. Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu Rev Neurosci 1984;7:309 –38. Maciewicz R, Fields HL. Pain pathways. In: Asbury AK, McKhann GM, McDonald WI, editors. Diseases of the nervous system: clinical neurobiology. Philadelphia/London: Saunders, 1986:930 – 40. Yaksh TL. Spinal opiate analgesia: characteristics and principles of action. Pain 1981;11:293–346. Hirai T, Jones EG. A new parcellation of the human thalamus on the basis of histochemical staining. Brain Res Brain Res Rev 1989;14:1–34. Benabid AL, Henriksen SJ, McGinty JF, Bloom FE. Thalamic nucleus ventro-postero-lateralis inhibits nucleus parafascicularis response to noxious stimuli through a non-opioid pathway. Brain Res 1983;280:217–31. Gerhart KD, Yezierski RP, Fang ZR, Willis WD. Inhibition of primate spinothalamic tract neurons by stimulation in ventral posterior lateral (VPLc) thalamic nucleus: possible mechanisms. J Neurophysiol 1983;49:406 –23. Zhang DX, Owens CM, Willis WD. Two forms of inhibition of spinothalamic tract neurons produced by stimulation of the periaqueductal gray and the cerebral cortex. J Neurophysiol 1991;65:1567–79. Gerhart KD, Yezierski RP, Wilcox TK, Willis WD. Inhibition of primate spinothalamic tract neurons by stimulation in peri-
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Deep Brain Stimulation for the Control of Pain Ira Garonzik, M.D., Amer Samdani, M.D., Shingi Ohara, M.D., and Frederick A. Lenz, M.D., Ph.D. 1 Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, Maryland 21287 Received May 11, 2001; accepted for publication May 14, 2001
The most common sites of deep brain stimulation (DBS) for relief of pain are the periaqueductal gray (PAG) for nociceptive pain and the principal sensory nucleus of the thalamus (Vc) for control of neuropathic pain. The mechanism of action of PAG stimulation seems to involve release of endogenous opiates, whereas the mechanism of Vc stimulation may involve either antidromic activation of the spinothalamic tract or orthodromic activation of thalamocortical relay cells. Success rates are higher for PAG stimulation than for Vc stimulation, but long-term success rates for both are in the range 40 to 60%. The rate of complications with DBS is lower in recent literature of DBS for movement disorders than in earlier literature of DBS for pain, suggesting that hardware modifications have decreased the rate of complications. DBS is an option in patients with chronic pain who are refractory to other modes of medical and surgical therapy. © 2001 Academic Press Key Words: pain; deep brain stimulation; thalamus; periaqueductal gray.
review is restricted to somatogenic as opposed to psychogenic pain (7). Somatogenic pain is classified into nociceptive and neuropathic pain. Nociceptive refers to pain arising from the activation of peripheral nociceptors and transmitted to the central nervous system through intact somatosensory pain pathways. Examples of nociceptive pain include pain of acute trauma and cancer pain secondary to invasion of bone. This pain responds well to opiates. Neuropathic pain refers to pain arising from injury to the nervous system either peripherally (deafferentation pain, e.g., diabetic neuropathy) or centrally (central pain, e.g., poststroke pain) (7). It has been proposed that this type of pain does not respond to opiates (8), although further study of this proposal may be required (9, 10).
Electrical stimulation of subcortical structures in the brain (deep brain stimulation, DBS) for pain control was first reported in the 1950s when hypothalamic nuclei were stimulated for treatment of chronic pain (1, 2). The relief of pain with chronic electrical stimulation of sensory thalamic nuclei was first reported by Mazars et al. (3). A few years later mesencephalic stimulation-evoked analgesia was reported in chronic pain patients (4, 5). During the ensuing decades, the sensory thalamus and periaqueductal gray (PAG) became the most frequent targets for stimulation. These initial surgeries were based on studies in animals. Since that time, potential mechanisms for stimulationevoked analgesia have been proposed, based partly on the clinical results of retrospective studies of stimulation-evoked analgesia in humans (4, 5). The International Association for the Study of Pain’s Classification of Pain defines pain as an unpleasant sensory or emotional experience associated with actual or potential tissue damage or that which is described in terms of such damage (6). Chronic pain is pain that occurs daily over a 6-month period (6). This
DBS FOR PAIN RELIEF: MECHANISMS OF ACTION In 1969, Reynolds demonstrated that focal stimulation at the lateral margin of the PAG in rats prevented nociceptive responses during abdominal surgery without concomitant drug administration (11). These results were confirmed by Mayer and co-workers (12). Subsequently these effects were reported to be reversible with the administration of opioid antagonists (4).
1
To whom correspondence should be addressed at Department of Neurosurgery, Meyer Building 7-113, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287-7713. Fax: (410) 6149877. E-mail: [email protected]. 1525-5050/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
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S56 Endogenous opioids were elevated in the third ventricle after PAG stimulation (13, 14) although the mechanism of this effect might not be due to release of opioids by stimulation (15). Analgesia produced by stimulation of PAG occurs in the absence of other motor, sensory, or cognitive effects (4, 5). Several lines of evidence suggest that the mechanism of this analgesia involves a spinal connection (16, 17). First, while the PAG neurons rarely project directly to the spinal cord, they do project monosynaptically to the medullary nucleus raphe magnus (NRM). In turn, the NRM sends a strong serotonergic projection to the dorsal horn. Second, the analgesic effect of PAG stimulation is abolished by cutting descending pathways to the spinal cord. The PAG, medullary NRM, and dorsal horn all contain high levels of opiates and opiate receptors, suggesting that these structures mediate opiate-induced analgesia. In humans, infusion of opiates into the intraventricular or spinal subarachoid space causes analgesia (18). These results suggest that PAG stimulation evokes analgesia by activation of the medullary NRM, which sends a serotonergic projection to the dorsal horn. Opiates may be involved in the mesencephalic and spinal components of this pathway. The mechanism by which thalamic somatosensory stimulation provides pain relief is not fully understood. The target nucleus for this type of stimulation is the principal somatosensory nucleus known as ventral caudal (Vc) in humans and ventral posterior (VP) in other species, including monkeys (19) and rats. Benabid and co-workers found that stimulation of the VP of the rat inhibited responses to noxious stimuli of cells in a thalamic intralaminar nucleus (nucleus parafascicularis) through an opioid-independent mechanism (20). Furthermore, the inhibition did not appear to involve dorsal horn neurons of the spinal cord, because stimuli that inhibited nucleus parafascicularis neurons did not affect the responses of a limited sample of dorsal horn interneurons. Gerhart and co-workers demonstrated the inhibitory effect of thalamic stimulation on lamina I to V spinothalamic tract (STT) neurons (21). The mechanism of this effect was thought to involve either orthodromic or antidromic mechanisms. Thalamic stimulation might anterogradely activate cortex and hence produce STT cell inhibition through the corticospinal tract (21, 22). Alternatively, stimulation-evoked STT activation might antidromically activate collaterals to PAG, which projects to NRM or to the cells of origin of reticulospinal pathways (see above), or could antidromically activate collaterals to NRM. NRM has a serotonergic Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
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spinal projection that could inhibit STT cells (23). Alternatively, any of these descending systems could activate propriospinal systems or dorsal horn interneurons (21). Sorkin and co-workers have shown that electrical stimulation of the VPL nucleus elicited increases in extracellular serotonin concentration in the monkey spinal cord (24). They hypothesized that thalamic stimulation activated collaterals to the cells of origin of the NRM–spinal tract, which in turn released serotonin, a modulator of nociceptive transmission. Finally, abnormally increased rates of thalamic bursting are reported to occur in neuropathic pain states and might be related to the sensation of chronic pain (25, 26; cf. 27). Stimulation in Vc could block this activity and so relieve the pain. Thus a variety of mechanisms may explain the efficacy of Vc stimulation for the relief of pain.
PUBLISHED STUDIES OF DBS FOR PAIN Patient Selection and Surgical Technique Three large studies of DBS for the control of chronic pain have been recently published (28 –30). In all three studies, patients were selected for DBS if they experienced chronic pain unresponsive to medical or surgical therapies over many years and to treatment administered during an admission to a pain clinic. Additionally patients underwent a psychological assessment. Among these studies the most complete assessment included a Minnesota Multiphasic Personality Inventory (31) and interviews with the patient and his or her spouse (28). Patients were chosen for stimulation if there was no evidence of psychological issues or of “secondary gain or other maladaptive functional characteristics.” In the other studies, only selected patients underwent psychological assessment (29, 30). Patients judged free of significant psychopathology were subjected to a morphine test during which they blindly rated their chronic pain in response to intravenous administration of placebo and morphine sulfate (4). This test is based on the hypothesis that nociceptive but not neuropathic pain responds to opioids (9; cf. 8, 10). In one study, reversibility of analgesia with naloxone was taken as an additional indicator that the analgesia was opiate-mediated (28). If the morphine test dose produced a major change in pain ratings, then the patient was assumed to have noci-
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ceptive pain and was selected for PAG stimulation. If there was no major change in pain ratings and the patient had a neuropathic clinical picture, then the patient was assumed to have neuropathic pain without a major nociceptive component and was selected for thalamic stimulation. In one of these studies, some patients without a major change in pain ratings were thought to be tolerant of the opioid-mediated effect of such stimulation (30). There was some evidence to suggest that l-tryptophan administration may reverse this presumed tolerance to stimulation (32). Therefore all patients without a major change in pain ratings in response to morphine were given oral l-tryptophan over a 4-week period in an attempt to reverse the presumed opioid tolerance (30). The morphine test was then repeated and patients who experienced a major change in pain ratings at that time had electrodes implanted in PAG. Surgical targets for PAG were determined by different means in the three studies. All targets were determined relative to the anterior commissure–posterior commissure (AC–PC) line, a third ventricular radiologic landmark with a relatively fixed anatomic relationship to subcortical structures (33). Levy and coworkers targeted a point 1 mm below and 1 mm posterior to the posterior commissure and 3 mm lateral to the lateral wall of the third ventricle (29). Young and Rinaldi targeted a point 2 to 3 mm below the AC–PC line and 12 to 14 mm posterior to the midpoint (MC) of the AC–PC line and 2 to 3 mm lateral to the midline (28). Hosobuchi targeted a site at the level of the opening of the aqueduct into the third ventricle and 3 mm lateral to the midline (30). The correct target was identified by stimulation-evoked warmth, oscillopsia, loss of up-gaze, elevation of both heart rate and blood pressure, or pain relief (28 –30). If the electrode is implanted more ventrally and posteriorly, fear and anxiety are evoked by stimulation (30). Periventricular gray, which is slightly rostral to PAG, has been targeted as an alternative site to PAG in some studies. The periventricular gray is located 10 mm posterior to MC and at the vertical level of the AC–PC line and 3 to 4 mm lateral to the midline (28). Levy and co-workers described sites of thalamic targets for treatment of deafferentation pain (29). Targets for facial deafferentation pain in the Vc medial (facial representation of Vc) were chosen 8 mm posteriorly to the MC point, 8 mm lateral to the midline, and 1 to 3 mm above the MC point (29). Deafferentation pain of the extremities was treated by stimulation of Vc lateral (representation of the extremities) defined as a point 9 mm posterior to MC, 10 to 12 mm lateral,
and 2 to 3 mm above the MC point. Other studies (28, 30) stated that targets were calculated from standard atlas maps (33). All studies included a period of testing with the electrode attached to an externalized lead. Patients were stimulated at different electrode combinations, voltages, pulse widths, and frequencies until the optimal stimulation parameters for pain relief were determined (28 –30). The results of this period of postoperative testing were used to decide whether or not to implant the stimulator. However, none of these papers included their criteria for deciding to attach the electrode to a receiver or stimulator and implant the system. Results The study by Young et al. (28, 34) retrospectively reviewed 178 patients undergoing DBS for chronic pain over a 14-year period. Eighty percent of patients (n ⫽ 89) had permanent implantation of the system including the pulse generator and the lead. The remaining patients failed to obtain pain relief during the test stimulation period; therefore, the electrode was removed and no stimulator was placed. Young assessed pain relief based on the following three criteria: (a) patient’s subjective evaluation of pain relief (visual analog scale of intensity change of greater than 50% with stimulation (35)); (b) effect on patient’s narcotic usage; and (c) change in patient’s functional capacity (28). Of the 89 patients with a permanent implant, 62% experienced long-term relief of pain. According to this study, long-term relief was obtained among 70% of patients with nociceptive pain who had permanent implants as compared with 50% of patients with neuropathic pain who had permanent implants. Young and co-workers relied on screening tests such as response of pain to opiates and reversal of response with naloxone to determine electrode target location early in their experience with DBS for pain (34), but not later (28), when they implanted electrodes in both periventricular gray and Vc in most patients (28). The most effective combination of stimulation through these two electrode systems was determined during postoperative testing. They did not find oral tryptophan a useful agent against the development of tolerance to stimulation (28), in contrast to other reports (30). The second study reported the results of DBS for chronic pain in 141 patients who were followed for 80 months (29). These patients had a mean period of pain Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
S58 of 65 months before surgery. The patients were divided into two groups: deafferentation pain states (84 patients) and nociceptive pain states (51 patients). Although screening tests (morphine intravenous infusion and naloxone reversal) were not used consistently throughout the series, the combination of the morphine test with the patient’s clinical picture was used to determine the appropriate site of implantation (see Patient Selection and Surgical Technique). Patients with a positive response to the morphine test were considered candidates for PAG stimulation and those patients unresponsive to the morphine test and with the clinical picture of neuropathic pain were considered for thalamic stimulation. Patients with mixed clinical pictures had electrodes placed in both locations. Outcomes were measured at 6 weeks (initial) and then at a later date with a mean of more than 6 years (long-term). Success was measured by regular use of the stimulator for relief of pain. There was a 61% initial success rate and a 30% long-term success rate for patients with various forms of deafferentation pain (29). Patients with nociceptive pain states had a 56% initial success rate and a 32% long-term rate. Examination of the individual subgroups within the pain states revealed that the patients with anesthesia dolorosa and pain after spinal cord injury had very low long-term success rates (⬍20%), while those with peripheral neuropathies had a 50% long-term success rate. The third study, by Hosobuchi and co-workers, reviewed 122 cases of chronic pain treated with DBS (30). The follow-up period ranged from 2 to 14 years and the mean duration of chronic pain was 6.5 years. Stimulation was considered to be a success if pain was controlled and narcotics were discontinued. Functional capacity such as return to work was not used as a measure of outcome. The authors relied on screening tests to determine target location of the electrode. Ninety-six patients with deafferentation pain had stimulators placed in Vc and 52 (68%) had initial success while 44 (57%) had long-term success. Within the deafferentation group, patients with postcordotomy dysesthesia had the best long-term response, and patients with anesthesia dolorosa had the worst longterm outcome. Sixty-five patients with nociceptive pain had bilateral PAG implants and 50 patients (77%) reported long-term success. This group comprised predominantly patients with chronic back and leg pain secondary to degenerative disease of the lumbar spine and patients with cancer pain. Thirty-six patients had both thalamic and PAG stimulators placed. Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
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Of these 36 patients, 19 had chronic back and leg pain; the back pain responded better to thalamic stimulation and the leg pain responded better to PAG stimulation. Seventeen patients had central deafferentation pain that responded only to thalamic stimulation and not PAG stimulation.
Complications The most serious complication of this procedure is intracranial hemorrhage. In one series, hemorrhage occurred in 5 of 141 cases with 1 death; 2 patients were left with permanent neurologic deficits, and 2 patients had no sequelae (29). In another series, 3 ventricular and 2 intracerebral hemorrhages occurred among 122 patients (30). Two patients died of the hemorrhage. In the third study, 2 thalamic and 2 subdural hemorrhages were reported (28); none was fatal. The rate of intracranial hemorrhage was attributed to the rough outer profile of an older electrode (30). A lower rate of hemorrhage has been reported with introduction of a redesigned electrode widely used for treatment of tremor (36). Neurologic sequelae of stimulation occurred in 7% of cases (28), including eye movement disorders (diplopia, vertical gaze paresis, blurred vision, oscillopsia), hemineglect, and hemiparesis (28, 29). Transient hemior monoparesis, lethargy and confusion, and dysphasia not apparently related to stimulation were described in one study (29). Persistent headache occurred in 50% of cases in one series (29) but was not mentioned in the other series. Infections occurred in 5 to 12% of cases (28 –30). The majority of organisms were Staphylococcus species (29). Stitch and subgaleal infections were the most common infections (30). The use of antibiotics alone cured superficial infections (28) and hardware infections in three cases (28, 30). Removal of the system and treatment with antibiotics was successful in all cases in which this approach was tried (30). The most serious infectious complications were ventriculitis (Proprionobacterium) and subdural empyema (Staphylococcus aureus), each occurring in one patient (30). Technical problems were reported in all studies, including migration of the electrode (2–10%) and fracture of the insulation (3– 4%) (28 –30). Skin erosion of the connector between the electrode and the coupling lead was reported in 2% of cases (30). These complications were corrected by removal of the nonfunctional system or replacement of the system. The rate of these complications has decreased with the rede-
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signed electrode (36), although the length of follow-up with the newer lead is shorter.
3.
4.
SUMMARY 5.
A meta-analysis of 13 studies (1114 patients) evaluating DBS for the treatment of chronic pain has recently been reported (37). Fifty percent of patients had long-term successful pain relief overall. Of patients with nociceptive pain (n ⫽ 419), 60% had long-term success with DBS. Among these patients, 59% had long-term success with PAG stimulation whereas Vc stimulation was successful in none of the patients stimulated. Of patients with neuropathic pain (n ⫽ 644), 54% had long-term success with DBS overall. Among patients with neuropathic pain, the long-term success of Vc stimulation was 56% whereas PAG stimulation was successful in 23%. To summarize, DBS is carried out in the PAG for nociceptive pain and in the principal sensory nucleus, Vc, for control of neuropathic pain. Success rates are higher for PAG stimulation than for Vc stimulation, but long-term success rates for both are in the range 40 to 60%. Rates of complications and side effects in the early literature are high. These rates seem to be lower in the recent literature of DBS for movement disorders, suggesting that hardware modifications have been effective. Thus, these procedures are still an option in patients with chronic pain who are refractory to other modes of medical and surgical therapy. Finally, DBS has focused attention on the pain modulatory system and advanced our understanding of that system.
ACKNOWLEDGMENTS
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This work was supported by grants to F.A.L. from the NIH (NS39498 and NS40059). 20.
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