Deep Brain Stimulation for Pain

Relevant History of the Topic Including Developments Over the Past Decade

The application of neurostimulation to the management of chronic pain syndromes remains a significant challenge for chronic pain specialists. The origins of deep brain stimulation for intractable pain can be traced back to rodent studies in the 1950s. James Olds and Peter Milner implanted electrodes into various targets in the rodent brain, and found such powerful effects of positive reinforcement with electrodes targeted to the septal region that rodents would self-stimulate for prolonged periods whenever allowed to do so. Concurrent observations from clinical studies in which the septal nuclei, including the diagonal band of Broca, were stimulated in patients with schizophrenia confirmed the translational potential of neuromodulation for pain, as patients receiving septal stimulation experienced serendipitous analgesic side-effects ( ). There followed a period of intense preclinical and clinical investigation designed to elucidate further the mechanisms underpinning the powerful analgesic effects reported.

Patients suffering from intractable pain due to malignant oncological diseases and rheumatoid arthritis provided an ethically justifiable source of trial subjects, and septal region deep brain stimulation (DBS) for cancer pain proved moderately effective in early studies. Septal stimulation fell out of favor, however, despite some studies reporting success rates of 60%, and this led to the investigation of alternative deep brain targets for treatment of intractable pain. In subsequent years a wide range of intracranial targets were investigated, including the internal capsule ( ), the ventral posterolateral (VPL) and ventral posteromedial (VPM) sensory nuclei of the thalamus, the centromedian–parafascicular (CmPf) intralaminar region of the thalamus, the periventricular and periaqueductal grey (PVG/PAG), the nucleus accumbens, and the anterior cingulate cortex.

The first studies of thalamic stimulation in the 1960s were based on the historical hypothesis that stimulation of thalamic sensory nuclei would allow the “proprioceptive or epicritic” component of sensation to balance the “protopathic or nociceptive” pain system. The gate-control theory emerged to displace these classical pain theories and provided a conceptual framework for the investigation of sensory internal capsule and VPM–VPL stimulation for the modulation of deafferentiation and neuropathic pain ( ). Positive results with VPM lesioning supported early studies of VPM–VPL stimulation, which consistently demonstrated acute responses to stimulation followed by tolerance to stimulation and recurrence of pain. Reports of benefit in patients suffering from anesthesia dolorosa, complex regional pain syndrome, arachnoiditis, phantom limb pain, and nerve root avulsion confirmed the utility of thalamic stimulation in a wide range of chronic pain states ( ). However, early success rates of 60%–80% decreased to only 30%–40% in later responses, highlighting the need for further investigation.

Advances in the understanding of the endogenous opioid analgesic system led to the concept of “stimulation-produced analgesia” and stimulation of the lateral PVG or PAG. Successful relief from somatoform or nociceptive pain with PVG/PAG stimulation in humans was first reported in the late 1970s ( ). Despite evidence of tolerance to PVG/PAG stimulation, the 1970s and 1980s saw a rapid rise in the use of DBS for pain with over 1000 cases performed in a 16-year period. Indications for stimulation were multifarious and inconsistent, and included cancer pain, rheumatoid arthritis, complex regional pain syndrome, central poststroke and thalamic pain, spinal cord injury, atypical facial pain and trigeminal neuralgia, anesthesia dolorosa, postherpetic neuralgia, failed back surgery syndrome, brachial plexus injury, phantom limb pain, multiple sclerosis, and genital pain ( ).

This explosion of neurosurgical activity resulted in attention from the United States Food and Drug Administration (FDA), which requested the manufacturers of DBS technology to undertake formal clinical trials to determine the safety and efficacy of DBS for chronic pain.

Review of the Current Knowledge Base of the Topic

Medtronic reported results from a trial using its first-generation model 3380 DBS electrode in 1976. The trial was adversely affected by poor enrolment and high attrition rates. Subsequent analysis of the trial design revealed deficiencies in patient selection criteria resulting in a heterogeneous patient population, as well as inconsistencies in deep brain targets, the number of electrodes used, and stimulation parameters. Heavy criticism of this trial led to a second Medtronic study using a more advanced electrode in 1990 (model 3387). This trial was stopped after recruitment of 50 patients due to poor enrolment rates, high rates of patient withdrawal, and limited evidence of efficacy. Neither trial was able to satisfy the predefined endpoint criterion of more than 50% of patients achieving more than 50% pain relief. Medtronic chose not to seek FDA approval of its DBS system for analgesia, and DBS for pain was designated investigational and “off-label.”

The failure of these trials highlighted the importance of strict patient selection criteria, including psychological screening to exclude patients with psychogenic or factitious disorders, cognitive impairment, and psychiatric disease. These principles formed the basis for the contemporary multidisciplinary approach used in many centers continuing to use DBS as a therapeutic strategy for intractable pain.