Introduction

The pioneer neurosurgeon Lauri Laitinen once commented that “when one sets out to make a historical survey of surgical attempts to relieve the tremor and rigor in Parkinson disease, one cannot help feeling that it would have been a far easier task to list those nervous structures which have not been attacked.” Neurosurgical attempts to relieve intractable pain mirror his wry observation; all structures from peripheral nerve through dorsal root, spinal cord, midbrain, and thalamus to cingulate cortex have been first lesioned and later electrically stimulated or perfused with analgesics or anesthetics ( Fig. 22-1 ). Yet chronic pain continues to present a considerable burden to society, transcending many debilitating medical diseases, including cancer, stroke, trauma, and failed surgery. Its prevalence may be over 20%.

Structures in the pain neuromatrix targeted by ablative neurosurgery (red) and electrical stimulation or neuromodulation (blue) . DBS, Deep brain stimulation; PAG, periaqueductal gray.

The concept of ameliorating persistent pain by deep brain stimulation (DBS) originates from clinical studies over half a century ago. On the basis of septal self-stimulation experiments in rodents and reports of analgesia in patients receiving septal DBS for psychiatric disorders, Heath and Mickle postulated that stimulating the same area that produced pleasure might relieve pain. They successfully reduced a patient’s cancer pain over several weeks with intermittent stimulation. The findings were replicated by a case series using improved equipment a decade later.

Further impetus for DBS was provided in the mid-1960s by the theoretical paradigm shift initiated by Melzack and Wall’s gate control theory and advances in stimulator technology. The gate control theory was translated first into implantable peripheral nerve stimulators and then into spinal cord stimulation (SCS), developed by Medtronic (Minneapolis, Minn) into a commercially available permanently implantable device.

Identification of the periventricular and periaqueductal gray (PVG/PAG) regions as a target for DBS has its origins in animal research. Mayer and associates and Reynolds and others were able to perform major surgery in awake rodents using analgesia induced by PAG stimulation alone. Pain relief by PVG/PAG DBS was first reported in patients by Richardson and Akil and then Hosobuchi, Adams, and Linchitz. Evidence supporting ventroposterolateral and ventroposteromedial (VPL/VPM) thalamic nuclei and adjacent structures as putative targets for DBS came from ablative surgery, leading Hosobuchi, Adams, and Rutkin to treat anesthesia dolorosa with VPM thalamic DBS. Several others pioneered thalamic DBS, including Mazars, Merienne, and Cioloca, Mazars, Mazars, Roge, and Mazars and Adams and Fields who, along with Hosobuchi, also targeted the internal capsule. Observations from inadvertent localization errors and investigations into current spread from the PVG/PAG led others to target more medial thalamic nuclei, including the centromedian-parafascicular complex (Cm-Pf).

The rapid diffusion of electrical stimulation treatments for multifarious clinical indications by the mid-1970s led the U.S. Food and Drug Administration (FDA) to sponsor a symposium to evaluate their merits. Only pain treatments were documented to be both safe and effective, albeit in an era when the long-term complications of the then recently discovered levodopa on Parkinson disease were yet to be revealed. Crucial primate investigations elucidating basal ganglia functions and presaging a renaissance in DBS for movement disorders had also not yet been undertaken.

Despite the consensus, the U.S. Medical Device Amendments of 1976 compelled the FDA to request DBS manufacturers to conduct further studies to show the benefits of DBS for pain, and an additional ruling in 1989 required clinical trials to demonstrate safety and efficacy. Two multicenter trials were conducted, first in 1976 using the Medtronic Model 3380 electrode (196 patients) and then in 1990 with the Model 3387 (50 patients) that superseded it. The two studies were an amalgam of prospective case series from participating neurosurgical centers, neither randomized nor case controlled, and both suffered from poor enrollment and high attrition. Other shortcomings included heterogeneous case mixes with underspecified patient selection criteria and subjective and unblinded assessment of patient outcomes. Confounds arose from inconsistencies in deep brain sites stimulated, numbers of electrodes used per patient, and stimulation parameters chosen. Improvements made to the later Model 3387 trial included limiting deep brain sites stimulated to two per patient and using visual analog scores (VASs) to rate pain intensity for outcome assessment; but its included cases per center were tiny, with a mean of five and median of three patients treated.

Neither trial satisfied study criteria for efficacy of at least half of patients reporting at least 50% pain relief 1 year after surgery. Therefore U.S. FDA approval for analgesic DBS was not sought by the device manufacturer. However, intriguingly, the large numbers of patients lost to follow-up resulted in a steady increase with time in the proportion of patients with at least 50% pain relief; 2 years after implantation they comprised 18 out of the 30 remaining patients (60%) followed up in the Model 3380 trial and 5 out of the 10 in the Model 3387 trial (50%). Nonetheless, the trials resulted in the U.S. FDA giving DBS for pain “off-label” status, thus precluding its approval by medical insurers. As a consequence, few clinical investigations into DBS for pain using current technology and techniques have been reported.

In the last decade to our knowledge only five centers, three European and two Canadian, have published case series of more than six patients. In contrast, both other centrally implantable neurostimulation treatments for pain, SCS and motor cortex stimulation (MCS), have continued to yield research publications, albeit mostly of uncontrolled case series, with small randomized controlled, clinical trials in SCS emerging. Over 1300 recipients of DBS for pain have been reported compared to nearly 400 patients with MCS and nearly 4000 with SCS.

Our experience is that DBS is superior to MCS for selected refractory pain syndromes. Similarly we find DBS more appropriate than SCS for certain pain etiologies, although little published data exists comparing treatments by the same surgeon in the same group of patients. Two retrospective studies from the same group have compared all three modalities of central neurostimulation, but the results are obfuscated first by different treatments trialed both between and sequentially within patients and second by limited outcome information. A recent review has compared the three neurostimulatory therapies but did not include all contemporary DBS case series in its analysis. Over the last decade we have treated over 70 patients with analgesic DBS, regularly publishing results for many implanted and amenable to follow-up. Our experience is described, and results reviewed alongside other current studies to clarify the current status of DBS for pain.

Establishing Diagnosis and Indications/Contraindications

Historically, clinical approaches to DBS have sought to categorize patients first by cause of pain and second by dichotomizing the pain into such categories as nociceptive or deafferentation, epicritic or protopathic, peripheral or central. Such distinctions are largely unhelpful to patient selection since a gathering body of human functional neuroimaging and electrophysiological evidence confirms that chronic pain arises concomitant with centrally mediated changes related to neuronal plasticity, regardless of etiology. Thus it can be assumed that chronic pain refractory to medical treatment is largely central pain and thus neuropathic. The challenges to patient selection for DBS then become twofold: (1) the confirmation that the patient’s pain is neuropathic and neither factitious nor psychogenic, and (2) the selection of those with neuropathic pain who are likely to derive benefit from DBS.

Essential to the patient selection process is assessment by a multidisciplinary team consisting at a minimum of a pain specialist, neuropsychologist, and neurosurgeon. Comprehensive neuropsychological evaluation provides best practice in patient selection for DBS to exclude psychoses, addiction, and medically refractory psychiatric disorders and ensure minimal cognitive impairment. Quantitative assessment of the pain and health-related quality of life should be a requirement of the preoperative patient selection process. Our preference is to use both VAS (scale of 0 to 10) to rate pain intensity and the McGill Pain Questionnaire (MPQ) for pain evaluation, the latter giving additional qualitative information and including a quality of life assessment. We also assess quality of life using the Short Form 36 (SF-36) and VAS part of the Euroqol five-dimensional assessment tool (EQ-5D). The patient records his or her VAS twice daily in a pain diary over a period of 12 days. The 24 VAS scores are reviewed to ensure consistency and clarified with the patient if inconsistent. The EQ-5D, SF-36, and MPQ are administered by the pain specialist before surgery. The MPQ is repeated on a separate occasion independently by the neuropsychologist and scored using the ranked pain rating index. Our experience is that certain items of the MPQ can predict a positive response to DBS. In particular, over 80% of our patients who describe burning pain have found benefit from DBS, regardless of whether VPL/VPM, PVG/PAG or both are stimulated. We have published patient data linking resolution of burning pain with blood pressure reduction and long-term PVG/PAG DBS analgesia implicating cardiovascular changes in this type of pain and found heart rate variability changes consistent with sympathetic suppression and/or parasympathetic augmentation by PVG/PAG DBS ; but further multivariate analysis of other MPQ items, other brain targets, and other measurable cardiovascular parameters are required to elucidate further the phenomenon.

The specific etiology of the chronic pain appears less important to efficacy than its symptom history, which may involve hyperalgesia, allodynia, and hyperpathia. The pain must have a definable organic origin with the patient refractory to or poorly tolerant of pharmacological treatments. Surgical treatments may have been attempted (e.g., peripheral neuroablative or decompressive procedures for trigeminal neuralgia); however, we do not consider failure of other neurostimulatory therapies a prerequisite for DBS. Our preference is to trial DBS rather than SCS or MCS in carefully selected patients wherever the etiologies of chronic pain are consistent with neuronal reorganization at multiple levels of the central neuromatrix.

The greater body of clinical studies of SCS, coupled with ours and others’ lack of success with DBS for spinal injuries, favors SCS over DBS as a more appropriate first-line neurostimulatory intervention for spinal cord injury when central reorganization is likely to be mostly at a spinal level. However, our experience of DBS for pain after limb or plexor injury encourages us to consider DBS rather than SCS as first-line treatment for complex regional pain syndromes (CRPS). A 100% success rate in 13 implanted patients to date, together with a recent paradigm shift toward central brain reorganization with autonomic dysfunction as the mechanism underlying CRPS, supports the treatment both for brachial and lumbar plexus injuries and stump pain after amputation and for phantom limb pain.

Other pain etiologies for which we and others have obtained positive outcomes using DBS are stroke ; facial and head pain, including postherpetic trigeminal neuralgia and anesthesia dolorosa ; multiple sclerosis ; genital pain; and malignancy. These are listed for reference by etiology with implantation success rates shown in Fig. 22-2 ; however, we reiterate our position that to select patients for DBS primarily by etiology rather than by findings on history and examination and use of assessment tools is to oversimplify their chronic pain and risk poor outcomes. Rather than using inflexible selection criteria, our preference in patient selection is expert opinion after multidisciplinary assessment demonstrating quantitatively severe pain refractory to medication for at least 1 year, with significantly impaired quality of life and qualitative pain suggestive of neuropathic changes without predominantly spinal involvement. We find little merit in opiate or naloxone administration to determine suitability for DBS, although an historical literature exists. Medical contraindications to DBS include uncorrectable coagulopathy obviating neurosurgery and ventriculomegaly sufficient to preclude direct electrode passage to the surgical target.

Number of patients proceeding to full implantation by etiology at Oxford 1999 to 2008. Anes. Dol., Anesthesia dolorosa; FBSS/SCI, failed back surgery syndrome/spinal cord injury; Other, other trauma, malignancy, genital pain, multiple sclerosis.

Considering cephalalgias, we have also successfully treated cluster headache with DBS of the posterior hypothalamic nuclei and investigated it using multiple translational methods as for chronic pain. As we review comprehensively elsewhere, this debilitating condition has responded impressively to DBS in our initial experience and others’ and is worthy of multicenter, randomized controlled clinical trials. Further consideration of cluster headache is beyond the scope of this review.

Anatomy

DBS targets are contralateral to the painful side of the body. Currently used sites for DBS can be divided anatomically first into somesthetic regions of the ventrobasal thalamus (VPL/VPM) and second into more medial regions surrounding the third ventricle and aqueduct of Sylvius, including the gray matter (PVG/PAG) and medial thalamic Cm-Pf nuclei. Further anatomical distinction is redundant since accuracy of DBS placement for most practitioners is limited to ±2 mm at best by magnetic resonance imaging (MRI) and computerized tomography (CT) slice thickness.

Moreover, our ultimate adjustment of intracerebral electrode position is directed by awake patient reports of somesthetic localization during intraoperative stimulation. Such subjective information may alter the final electrode site by up to several millimeters from preoperative target coordinates. A guiding principle is the established somatotopic organization of the somesthetic thalamic and PVG/PAG regions. Human microelectrode studies reveal a mediolateral somatotopy in the contralateral ventroposterior thalamus, the head of the homunculus being medial and the feet lateral. Subjective observation of a rostrocaudally inverted sensory homunculus in contralateral PVG/PAG has been confirmed objectively by our human macroelectrode recordings of somatosensory evoked potentials. The PVG/PAG target is found at a point 2 to 3 mm lateral to the third ventricle at the level of the posterior commissure, 10 mm posterior to the midcommissural point. Its pertinent anatomical boundaries in the midbrain include the medial lemniscus laterally, the superior colliculus inferoposteriorly, and the red nucleus inferoanteriorly. Sensory thalamic targets are found 10 to 13 mm posterior to the midcommissural point and from 5 mm below to 2 mm above it. The VPM is targeted for facial pain only and found midway between the lateral wall of the third ventricle and the internal capsule; the arm area of VPL is 2 to 3 mm medial to the internal capsule and the leg area of VPL 1 to 2 mm medial to the internal capsule. The sensory thalamus is bordered by Cm-Pf nuclei medially; the internal capsule laterally; the thalamic fasciculus, zona incerta, and subthalamic nucleus inferiorly; the thalamic nucleus ventralis intermedius anteriorly; and the pulvinar thalamic nucleus posteriorly.

Basic Science

A wealth of electrophysiological, anatomical, and radiological evidence in humans and animals, reviewed elsewhere, establishes both PVG/PAG and ventrobasal thalamus as structures important to pain perception and the pathophysiology of chronic pain syndromes. The subtleties of hierarchical position and behavioral function of individual brain structures, whether sensory-discriminative, attentional, motivational-affective, or hedonic, are much debated. However, the consensus is toward a pain neuromatrix also involving spinal cord; posterior hypothalamus; amygdala; and neocortical structure, including somatosensory, insular, anterior cingulate, and prefrontal cortex. Whether pain control is top-down or bottom-up in its hierarchy is unresolved and often depends on the experimental paradigm used. Our human electrophysiological studies of neuronal coherence have used somatosensory-evoked potentials and Granger causality predictive modeling to suggest that PVG/PAG exerts ascending modulation on VPM/VPL in a bottom-up model of pain processing, a finding that functional MRI would be unable to confirm because of insufficient temporal resolution.

Central to the rationale for DBS is the concept of aberrant neuronal firing at the target sites concomitant with the chronic pain. Human and animal electrophysiological experiments show increased thalamic neuronal firing in pain. Comprehensive reviews of electrophysiological studies conclude that the mechanisms of analgesic stimulation are not clearly delineated. From insights revealed by basal ganglia microelectrode recordings and DBS for movement disorders reviewed elsewhere, we postulate that altered rhythmic activity in VPL/VPM and PVG/PAG neurons is likely to play an important role in the pathophysiology of central pain. At either target our clinical experience is that in general DBS at lower frequencies (≤50 Hz) is analgesic and at higher frequencies (>70 Hz) hyperalgesic, supporting a dynamic model whereby synchronous oscillations in discrete neuronal populations centrally modulate chronic pain perception. Therefore analgesic DBS may either disrupt pathological high-frequency synchronous oscillations or, more likely, augment pathologically diminished low-frequency synchronous oscillations in the thalamic and reticular components of a reticulothalamocorticofugal pain neuromatrix. We have shown a positive correlation between analgesic efficacy at either DBS site and the amplitude of slow frequency (<1 Hz) VPL/VPM local field potentials (LFPs), allowing for physiologically modulated artifact. We now also have early evidence that patients off DBS have characteristically enhanced low-frequency (8 to14 Hz) power spectra of both PVG/PAG and VPL/VPM LFPs when in pain. Further research is required to elucidate if such neuronal signatures could aid patient selection, in particular if combined with technical advances in noninvasive functional neuroimaging and electrophysiological techniques such as single photon emission computed tomography (SPECT) and magnetoencephalography (MEG) to characterize functional neuronal connectivity.

The PVG/PAG is a structure optimally sited anatomically to integrate interoceptive function, both from adjacent mesencephalic cardiovascular centers and more distal pain processing areas. Its autonomic effects have been well studied in animals, and changes noted with DBS. We have demonstrated a positive correlation between degree of analgesia in patients receiving PVG/PAG DBS and magnitude of blood pressure reduction and shown that, whereas dorsal PAG stimulation can acutely elevate blood pressure, ventral stimulation reduces it. Such findings advance investigations for objective markers of chronic pain and also potential selection of patients who may respond best to PVG/PAG DBS. Indeed our investigations into heart rate variability changes and preliminary findings from ambulatory blood pressure monitoring that such blood pressure changes are sustained may provide objective somatic measures of efficacy that correlate to subjective rating scales. Detailed autonomic testing using such equipment as tilt-tables, Portapres, and real-time VAS recording is underway to elucidate such possibilities.

Current thinking is that ventral PVG/PAG DBS engages analgesia commensurate with passive coping behavior, whereas dorsal PVG/PAG DBS may involve “fight or flight” analgesia with associated sympathomimetic effect. However, evidence to substantiate the conjecture that PVG/PAG DBS acts via augmenting endogenous opioid release is contentious. The hypothesis arose from animal experiments revealing stimulation-produced analgesia reversed by naloxone and human studies that also showed elevated levels of cerebrospinal fluid enkephalins and endorphins with DBS. However, the cerebrospinal fluid measures were artifactual, and double-blinded investigation in humans has revealed no cross-tolerance between DBS and morphine and similar reversibility between naloxone and saline placebo, confirming others’ findings. Our preliminary human studies agree that naloxone and placebo effects on DBS are similar, questioning an opioid-dependent mechanism. Furthermore, naloxone and saline seem to have distinct and different effects on the low-frequency power spectra of PVG/PAG and VPL/VPM LFPs, suggesting that both opioids and contextual influences can modulate neuronal responses in the pain neuromatrix independent of DBS, in agreement with the dynamic rate model proposed previously. However, naloxone can potentiate acute withdrawal and psychosis in long-term users of opiate analgesia. Thus we advise against its administration during stereotactic neurosurgical procedures in awake patients.

An obstacle yet to be surmounted in the quest to understand the mechanisms of analgesic stimulation is the lack of adequate animal models of chronic pain. In addition to their limited homology in chronic pain paradigms, the smaller brains of rodent and murine models increase targeting inaccuracies, in particular for small brainstem structures such as PVG/PAG. Such experience emphasizes the important opportunities presented by patient-based translational research into DBS to study the mechanisms underlying its efficacious analgesia.

Guidelines

There are no recent North American guidelines for DBS for pain because of its off-label indication in the United States. We have contributed to the European Federation of Neurological Societies’ guidelines on neurostimulation therapy for neuropathic pain, which concludes that, because of the few recent case series published, DBS should be limited to specialist centers willing to study and report their outcomes.

Imaging, Equipment, and Technique

Informed written patient consent is obtained after detailed explanations of the risks and potential benefits of the procedure and counseling for its duration of approximately 2 hours under moderate sedation and local anesthesia with the head fixed and cranial stereotaxis applied ( Fig. 22-3 ). Our operating theatre setup is shown in Fig. 22-4 . A week or more before surgery, patients have a T1 weighted MRI scan. For surgery a Cosman-Roberts-Wells (CRW) base ring is applied to the patient’s head under local anesthesia. A stereotactic CT scan is then performed, and the MRI scan is volumetrically fused to it using computerized image fusion and stereotactic planning programs to eliminate spatial distortions that arise from magnetic field effects. The coordinates for the PVG/PAG and VPL or VPM and entry trajectory are then calculated ( Fig. 22-5 ). A frontal trajectory avoiding the lateral ventricles is preferred. DBS targets are described in the previous anatomy section.

Deep brain stimulation for pain caseload at Oxford during the last decade showing explantation rates. These have remained constant at 23% during the last decade.

Theater setup. During awake stereotactic surgery a portable recording rig is used for macroelectrode local field potential (LFP) recording if required. LFPs can be recorded from each of the four contacts (0 to 3) of the deep brain electrode (inset right).

Fused T2 weighted preoperative MRI and postoperative CT images highlighted using heat mapping (axial, coronal, and sagittal clockwise from bottom left) showing left PVG/PAG electrode placement. Three-dimensional reconstruction of electrode trajectory is shown bottom right. PVG/PAG, Periventricular and periaqueductal gray.

After a 3-cm parasagittal scalp incision and separate 2.7-mm twist drill craniotomy per electrode, both VPL/VPM and PVG/PAG have been implanted to date with Medtronic Model 3387 quadripolar electrodes. PVG/PAG is implanted first; excellent intraoperative analgesia obviates implantation of a second electrode in VPL/VPM in up to half of patients, in particular those with marked thalamic damage (e.g., following stroke). Thus most of our cohorts have received PVG/PAG or dual-target DBS ( Fig. 22-6 ). The minority who have received VPL/VPM DBS alone have either not experienced efficacy or had side effects with a trial of PVG/PAG DBS. Final electrode position is determined by intraoperative clinical assessment reliant on subjective reporting by the awake patient; microelectrode recording is not routinely used. Bipolar 5- to 30-Hz stimulation is performed initially, pulse width 100 to 450 µs, amplitude 0.1 to 3 V. VPL/VPM stimulation aims to supplant painful sensation by pleasant paresthesia, and PVG/PAG stimulation seeks to induce a sensation of warmth or analgesia in the painful area. Adjustment is primarily somatotopic so as to evoke appropriate topographic responses, but the assessor should be alert to pyramidal signs suggesting capsular involvement with VPL/VPM DBS and with PVG/PAG DBS for oscilliopsia and reports of visual disturbances caused by superior collicular involvement or facial paresthesia arising from medial lemniscus stimulation. Each electrode is fixed to the skull by a miniplate, and its leads externalized parietally via temporary extensions. Immediately after surgery a further stereotactic CT is performed and co-registered as before to confirm electrode position. MRI may be performed after surgery during the week before implantable pulse generator (IPG) insertion for further anatomical target corroboration.

Number of patients proceeding to full implantation by etiology. PVG/PAG, Periventricular and periaqueductal gray matter.

After a week of postoperative clinical assessment, a decision is made whether to permanently implant the electrodes in a second operation under general anesthesia. They are connected to an IPG implanted subcutaneously, usually infraclavicularly or alternatively intraabdominally in subcutaneous fascia. Medtronic Synergy or Kinetra has been used to date. Our surgical technique is detailed further elsewhere.

Patient Management/Evaluation

All electrodes are externalized for a week of trial stimulation. During this period the patient records VAS scores at least twice daily and is kept blinded to DBS settings. Targets are trialed individually for 1 to 2 days using the stimulator parameters described to determine which settings of quadripolar electrode contact polarities confer maximum analgesia to the optimal somatic region. Monopolar stimulation is also trialed if bipolar settings fail to give pain relief. After this period both electrodes are trialed together for 1 to 2 days. If the patient is satisfied with the degree of pain relief obtained, full implantation of the efficacious electrode(s) is performed, and DBS commenced at the optimized stimulation parameters. In general, we do not decide between permanent implantation of PVG/PAG, VPL/VPM, or dual-site stimulation on any criteria other than demonstrable efficacy in each individual patient.

Another method favored for evaluating analgesia in single cases and small groups of patients is the N-of-1 trial. A randomized, placebo-controlled intrapatient trial is conducted whereby the patient receives pairs of treatment periods during which each intervention, be it DBS on or off or different stimulation targets or parameters, occurs once. The order of treatments is randomized, and the effects of treatment or placebo can be compared between treatment periods. We have demonstrated the validity of N-of-1 trials using the VAS, and their concordance with overall MPQ has been demonstrated for VPL/VPM, PVG/PAG, and dual-target DBS. Blinding and randomization methodologies have also been adopted by others to investigate the efficacy of thalamic DBS. However, the process is labor intensive for the clinician and thus not routinely practicable with limited clinical resources.

Patients ideally leave the hospital the day after IPG implantation and we endeavor to follow their progress with clinic appointments at 1 month, 3 months, 6 months, and annually thereafter. Initially they are given a pain diary to record their VAS and stimulator settings weekly for review at follow-up. In addition to being able to switch the DBS on and off at will, they are usually only given control over its voltage, which is typically limited by the clinician to a maximum efficacious amplitude of up to 6 V.

Outcomes Evidence

Several reviews of DBS for chronic pain have been published, many expert, some commentaries, several systematic. * Our systematic searches have identified a number of primary studies. ^†

* See reference numbers .

See reference numbers .

Table 22-1

Summary of Prospective Case Series of Thalamic and Periventricular Deep Brain Stimulation for Pain

Study Reference	Number of Patients Implanted	Deep Brain Target	% Success: Long-Term (Initially)	Follow-up Time (months): Range (mean)	Evaluation Method Used
	84 121	PVG/PAG VPL/VPM	0 69	N/A	Verbal report
	30	PVG/PAG	70	1-46 (18)	Self report; NRS
	7	PVG/PAG	16		Nociceptive stimuli
	6	PVG/PAG	33	6-42	Verbal report
	28	PVG/PAG	76	1-33 (14)	N/A
	24	VPL/VPM	67	1-47 (10)	Verbal report; HRQoL; analgesic use
	26 20	PVG/PAG VPL/VPM	28	6-54	Three category rating
	48 12	PVG/PAG VPL/VPM	79	6-42 (36)	VAS
	24	VPL/VPM	63	N/A	Three category rating; activity; analgesic use
	41	PVG/PAG VPL/VPM	41	N/A	VAS; HRQoL
	65 77	PVG/PAG VPL/VPM	77 (82) 58 (68)	14-168	Verbal report; analgesic use
	141	PVG/PAG VPL/VPM	31 (59)	24-168 (80)	Verbal report
	89	VPL/VPM	67	N/A	VAS; verbal report; analgesic use
	36	VPL/VPM	30 (61)	(48)	Nociceptive stimuli
	25 43 12	VPL/VPM Both Other	14 (overall)	n/a	Verbal report
	178	PVG/PAG VPL/VPM	50 (80)	12-180 (90)	VAS; analgesic use; HRQoL
	68	PVG/PAG VPL/VPM	62 (78)	6-180 (78)	VAS, MPQ
	12	PVG/PAG	n/a	n/a	N/A
	8 3 45	PVG/PAG VPL/VPM Both	63 33 38	6-66	N/A
	6	VPL/VPM	83	(42)	NRS, nociceptive and placebo stimuli
	21	PVG/PAG VPL/VPM	24 (62)	2-108 (24)	VAS, use of DBS
	47	PVG/PAG VPL/VPM	39 (74)	1-44 (19)	VAS, MPQ, HRQoL

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