Featuring Philippe Berenger, MD
Nearly a dozen clinical practice guidelines on managing low back pain have been published in the past decade, yet there’s little evidence they’ve altered physician practice, improved patient outcomes or enhanced the value of care. That needs to change, says Philippe Berenger, MD, a staff physician in Cleveland Clinic’s Department of Pain Management.
“Promising new treatments for low back pain are constantly emerging, but many ultimately prove no more effective than past treatments,” he explains. “It’s critical to confirm that new therapies are supported by evidence and that clinical guidelines are followed to ensure optimal outcomes and cost-effective care.” Cleveland Clinic is taking on these challenges in two broad ways: with its new Spine Care Path to systematically reduce variation from evidence-based care, and via highly integrated, enterprise wide collaboration for the most challenging cases.
FROM VOLUME TO VALUE
The Cleveland Clinic Spine Care Path is a process-based tool designed for integration in the electronic medical record (EMR) to guide clinical work flow and help providers make evidence-based guidelines operational (see sidebar below). The care path was developed by Cleveland Clinic’s Center for Spine Health with input from Department of Pain Management staff like Dr. Berenger. One goal was to match appropriate treatments and providers to patients at various points along the care continuum for low back pain.
“We know acute back pain is common and often resolves with simple therapy or even no therapy,” Dr. Berenger says. “For patients without red flags, imaging is rarely required.” These patients may be best served through prompt access to care from physical therapists or nurse practitioners as entry-level providers. When pain persists beyond four to six weeks, the care path defines when referral to spine or pain specialists, spine surgeons or behavioral health providers is indicated. Another objective was reducing variation from evidence-based practice, which can be costly — and potentially harmful — without benefiting patients. “Providing care along a specific pathway helps avoid overtesting and excessive imaging,” Dr. Berenger notes.
HOW THE CARE PATH WORKS
Under the care path, when patients first present with acute back pain, they are evaluated for red flags suggestive of malignancy or other underlying disease. If red flags are ruled out, management is guided through a consistent, evidence-based protocol that follows these principles:
- Imaging is not necessary
- Activity is encouraged as tolerated
- Simple nonopioid analgesics are used as needed
- For persistent pain, follow up as needed in approximately four weeks (with possible referral to a spine or pain specialist at that point, if indicated)
Central to the process is the Spine Care Path’s integration into the EMR, which assists the clinician by flexibly encouraging adherence to guidelines-based care at every turn. Likewise, patient-reported data are fed into the EMR at each visit as patients complete validated pain and function questionnaires on tablet devices using a Cleveland Clinic-developed intake tool called the Knowledge Program. This allows patient progress to be monitored and correlated with process measures like imaging use and appropriate referrals, which will enable the care path to be continually improved over time.
IF CONSERVATIVE CARE COMES UP SHORT
Identifying the pain generator is important in guiding low back pain management, especially in cases that don’t respond to conservative measures like first-line drugs or physical therapy. Isolating the pain generator is often an initial focus when patients require referral to a spine or pain specialist.
For such patients, Dr. Berenger may use diagnostic blocks (e.g., facet blocks, joint anesthetic injections, discograms or medial nerve branch blocks) to isolate the pain generator and guide interventional management. Once a pain generator is identified, some of these same blocks can be used therapeutically at the implicated disk or nerve, typically along with physical therapy. Patients often respond to such management and can be maintained on it or gradually weaned from it.
Those who do not gain adequate relief may be referred for further evaluation, including for spine surgery or enrollment in a clinical trial for interventions such as disk biacuplasty or minimally invasive neurostimulation (see sidebar below).
TAKING TREATMENT BEYOND THE BACK
Dr. Berenger and colleagues also comprehensively evaluate for confounding conditions, such as fibromyalgia or rheumatologic disease, through blood tests, X-rays and consults. “Even when back pain can be attributed to structural problems, confounding conditions or psychosocial issues still need to be addressed for the patient to recover and regain function,” he says. That’s when Cleveland Clinic’s collaborative approach — formalized under the Spine Care Path — can yield the greatest benefits. “We offer enterprise wide evaluation for challenging cases, drawing on the Center for Spine Health, the Department of Pain Management, our comprehensive Chronic Pain Rehabilitation Program, neurologists, behavioral health providers and others,” Dr. Berenger notes. “Patients can expect a better experience — and much less jumping between unconnected providers — with all these specialists with different skill sets cooperating to deliver an outcome that’s meaningful to them.”
NEUROSTIMULATION FOR LOW BACK PAIN: MINIMALLY INVASIVE APPROACHES EMERGING
In the most refractory cases of low back pain, Dr. Berenger and colleagues may refer patients for spinal cord stimulation, including two new minimally invasive modalities being offered at Cleveland Clinic:
- A percutaneous delivery system for neurostimulation as an alternative to lead placement by laminotomy/laminectomy
- An epidural approach to dorsal root ganglion (DRG) stimulation allowing precise stimulation of anatomic targets implicated in chronic pain
“Neurostimulation is a great modality for treating intractable leg pain, but it’s traditionally been difficult to use for axial low back pain,” says Department of Pain Management specialist Nagy Mekhail, MD, PhD. For stimulation to reach the target nerves, it must penetrate the cerebrospinal fluid, which is thickest in the thoracic region. The energy delivered by neurostimulation often is insufficient to broach this barrier. Until recently, overcoming this obstacle meant placing multiple leads or implanting paddle leads through laminotomy/laminectomy surgery.
The percutaneous approach to neurostimulation (Epiducer™ Lead Introduction System, St. Jude Medical) allows introduction of multiple leads without interfering with the integrity of the spine by laminotomy or laminectomy and without the major incisions typically required to place more than one lead, says Dr. Mekhail. The single entry port accommodates up to three leads, which can be configured to tailor neurostimulation to a patient’s unique pain patterns.
The percutaneous lead delivery system is FDA-approved and has successfully relieved chronic low back pain in a handful of patients treated so far by the Department of Pain Management, says Dr. Mekhail. “Candidates are patients with intractable back pain (unresponsive to conventional spinal cord stimulation) not caused by correctable pathology or with epidural scarring,” he notes.
The other minimally invasive approach, DRG stimulation, preferentially targets the primary sensory neurons responsible for chronic pain in the lower extremities, including low back pain. It is currently available in the U.S. only via clinical trials. Cleveland Clinic is participating in a multicenter trial of DRG stimulation in patients with chronic intractable leg pain secondary to complex regional pain syndrome or peripheral causalgia.
In DRG stimulation, which was profiled in last year’s Pain Consult, electrodes with contacts are threaded via the epidural space through the intervertebral foramen to the dorsal root ganglia. The electrical fields generated selectively stimulate different areas of the ganglia.
Cleveland Clinic researchers pursue a potentially treatable common pathway.
Promising research by Cleveland Clinic investigators demonstrates that microglial inflammation is a common pathway — and a potentially treatable one — for neuropathic pain and other treatmentresistant neuroinflammatory conditions, including Alzheimer disease (AD).
“Microglial inflammation is a mechanism of many CNS disorders — neuropathic pain, AD, multiple sclerosis, parkinsonism, you name it,” says lead researcher Mohamed Naguib, MD, of Cleveland Clinic’s Anesthesiology Institute, which includes the Department of Pain Management. His team has synthesized a molecule called MDA7, a cannabinoid type 2 (CB2) receptor-selective agonist, to inhibit microglial inflammation in hopes of effectively treating neuropathic pain and other conditions. “MDA7 prevents microglial activation and recruitment, which represent the elemental pathway of microglial inflammation,” explains Dr. Naguib.
EFFICACY IN A RODENT MODEL OF CHEMO- INDUCED NEUROPATHIC PAIN
The researchers demonstrated as much in a 2012 paper in Anesthesia and Analgesia (2012;114:1104-1120)reporting findings from a rodent model of paclitaxel-induced neuropathy, which is associated with activation of microglia followed by the activation and proliferation of astrocytes and the expression and release of pro-inflammatory cytokines. They found that MDA7 prevented paclitaxelinduced allodynia in rats and mice in a dose- and time-sensitive fashion without compromising paclitaxel’s anticancer effects. MDA7’s anti-allodynia effect was absent in CB2–/– mice and was countered by CB2 antagonists, which suggests it directly involves CB2 receptor activation.
Because all neuropathic pain shares the mechanism of microglial inflammation, Dr. Naguib expects the same effect in neuropathic pain types outside the chemotherapy setting. “We started with chemotherapy- induced neuropathy because it’s an area of unmet therapeutic need,” he says.
SIMILAR EFFICACY IN CRPS
His team recently finished a study using a vascular occlusion model in the rat to replicate another form of chronic pain with a microglial inflammation mechanism, complex regional pain syndrome (CRPS). MDA7 was again highly effective, both at the molecular level and in terms of phenotypic response. They expect to submit the CRPS study for publication this year.
PROMISE FOR ALZHEIMER DISEASE
The wider biomedical community learned of the team’s work via an exciting study in February’s Nature Neuroscience (2014; 17:223-231) linking microglia-mediated inflammatory changes in a postsynaptic protein, neuroligin 1, to amyloid-associated memory deficiency in rodents. Current models of AD hold that amyloid plaques accumulate in the brain, overwhelming the microglia that serve as the nervous system’s main form of active immune defense. When the microglia cannot clear out amyloid rapidly enough, they become inflamed, which leads to gene modifications in the brain.
“As our research into microglial inflammation advanced, it became clear how important this inflammation is to a variety of disease processes, which led down the Alzheimer path,” says Dr. Naguib. His team’s Nature Neuroscience study showed that the microglial inflammation induced gene changes in the brain include suppressed expression of the neuroligin 1 protein — and that this suppression leads to hippocampal glutamatergic dysfunction and memory deficiency in rodents. The effects were ameliorated by inhibiting microglial activation. “These findings link neuroinflammation, synaptic efficacy and memory, thus providing insight into the pathogenesis of amyloid-associated diseases,” the researchers concluded.
Dr. Naguib notes that much research remains, but the findings suggest that MDA7 represents a promising new therapeutic approach to AD and other conditions involving microglia-mediated neuroinflammation, such as multiple sclerosis and Parkinson disease.
In the near term, the researchers are focused on gaining funding to move MDA7 into phase 1 human studies for chemotherapy-induced neuropathy, which they hope to begin by 2015. Studies of MDA7 in animal models of AD will take longer, due to the longitudinal nature of AD, but Dr. Naguib says the team is committed to pursuing that research as well.