The observations add to previous studies suggesting that “progressive exercise training markedly decreased diabetes associated neuropathic pain,” write Yu-Wen Chen, PhD, of China Medical University, Taichung, Taiwan, and colleagues. The link to Hsp72 offers a clue as to how exercise can prevent or slow the development of neuropathy—a major complication of diabetes.

Exercise Reduces Diabetic Nerve Pain in Rats
Neuropathic pain is a common and difficult-to-treat type of pain related to nerve damage—most commonly caused by diabetes. Affecting about half of patients with diabetes, diabetic neuropathy causes symptoms such as numbness, tingling, or pain in the arms and legs.

Dr Chen and colleagues examined the effects of exercise on neuropathy caused by chemically-induced diabetes in rats. For a few weeks after induction of diabetes, some animals were assigned to a progressive treadmill exercise program.

Within two weeks, the diabetic rats that did not exercise showed signs of diabetic neuropathy, based on observable pain behaviors. These included abnormal responses to temperature and pressure (thermal and tactile hypersensitivity)—both characteristic of neuropathic pain.

“In contrast, diabetic rats undergoing exercise demonstrated delayed progress of tactile and thermal hypersensitivity,” Dr Chen and colleagues write. The reduction in painful diabetic neuropathy was associated with lesser increases in blood glucose levels after induction of diabetes.

Previous studies have suggested that neuropathic pain may be related to expression of certain inflammation-promoting cytokines—such as tumor necrosis factor-alpha and interleukin-6—which might be reduced by exercise. In the new experiments, expression of TNF-alpha and IL-6 in nerve tissue were significantly increased after induction of diabetes, with no difference for exercising versus non-exercising animals.

Findings Suggest Role of Heat Shock Protein
However, diabetic rats assigned to exercise showed increased expression of Hsp72 in nerve tissues. Hsp 72 is one of a family of heat shock proteins that play essential roles in protecting against cellular damage caused by various types of stress (including heat stress). Previous experiments have shown protective effects of Hsp72 in other conditions, including neuropathy caused by mechanical nerve injury.

Exercise is commonly recommended for patients with various types of chronic pain, and is routinely prescribed as part of treatment to control diabetes. A growing body of evidence suggests that exercise may also have beneficial effects in reducing painful diabetic neuropathy.

The new study provides support for the concept that exercise can slow the progression of diabetic neuropathy. In the animal experiments, exercise had short-term effects on abnormal responses to pain and temperature, although long-term responses were unchanged.

The study also adds new evidence that exercise may protect against diabetic neuropathy by suppressing induced blood sugar levels while increasing expression of Hsp72 in nerve tissues. The results may present new opportunities for developing new, nondrug approaches that can “delay or protect against the development of diabetic peripheral nerve complications,” Dr Chen and coauthors conclude.

Read the article in Anesthesia & Analgesia

Under the proposed label changes, opioids would no longer be indicated for moderate noncancer pain. The petition notes that moderate to severe pain is the FDA-approved indication for nearly all instant-release opioids as well as extended-release versions when 24/7 pain relief is needed for a long stretch of time. Such “overly broad indications” imply that the FDA has established that long-term use of opioids is safe and effective, the petition states. “An increasing body of medical literature suggests that long-term use of opioids may be neither safe nor effective for many patients, especially when prescribed in high doses.”

In addition, the maximum daily dose would be the equivalent of 100 mg of morphine, and the maximum duration for continuous daily use would be 90 days under the proposed label changes. Both limits would apply to noncancer pain.

One of the petitioners, Andrew Kolodny, MD, president of Physicians for Responsible Opioid Prescribing, told Medscape Medical News that the label changes would not prevent physicians from prescribing opioids at doses and durations that they deem appropriate for patients on a case-by-case basis. However, the changes would limit claims that drug companies can make about their products.

“Right now, drug companies are promoting long-term opioids as proven safe and effective for chronic pain,” he said. “They’ll promote [them] for lower back pain, fibromyalgia, osteoarthritis, whatever they want…because the current label is like a blank check.”

“By prohibiting the aggressive marketing, we can reduce the overprescribing,” said Dr. Kolodny. Physicians who understand that opioids are not necessarily safe and effective long term may resort to other treatments such as behavior modification, physical therapy, and weight loss, he added.

Other physicians signing the petition include

• Roger Chou, MD, Associate Professor of Medicine, Oregon Health & Science University
• Edward Covington, MD, Director, Neurological Center for Pain, Cleveland Clinic
• Stuart Gitlow, MD, MPH, Acting President, American Society of Addiction Medicine
• Elinore McCance-Katz, MD, PhD, Professor, Department of Psychiatry, University of California–San Francisco
• Nirav Shah, MD, MPH, Commissioner, New York State Department of Health
• Sidney Wolfe, MD, Director, Health Research Group at Public Citizen

Label Change Called Necessary for Effective REMS

The petition to revise the label of opioid analgesics comes on the heels of a new FDA initiative to help turn the tide of the prescription painkiller epidemic, which is causing more fatal overdoses than cocaine and heroin combined, according to the US Centers for Disease Control and Prevention. Earlier this month, the FDA approved a Risk Evaluation and Mitigation Strategy (REMS) for extended-release and long-acting opioids prescribed for moderate to severe chronic pain. More than 20 opioid manufacturers must make available to prescribers continuing education programs on the proper use of these drugs. This education will be funded through grants from manufacturers to continuing medical education providers, who will develop the training based on a blueprint for content provided by the FDA and will deliver the training.

Dr. Kolodny told Medscape Medical News that the REMS for opioids “isn’t going to help and could potentially make things worse.”

Without the label change sought by his coalition, he said, the REMS curriculum would still leave doctors “with the false impression that long-term opioid therapy was proven safe and effective.”

One company that would be affected by the envisioned label change is Purdue Pharma, the maker of controlled-release oxycodone (OxyContin), which is indicated for moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period. When asked to comment on the petition to the FDA, Purdue Pharma issued a statement saying, “[The] FDA, its advisory committees, and numerous medical experts maintain that the current indications for long-acting opioids are appropriate.

“We agree with the FDA that prescribing information for any medication should be subject to ongoing review and modification to the extent that compelling medical evidence emerges,” the company added.

Ensure Opioid Availability for Legitimate Need, Cautions Pain Expert

One pain expert interviewed by Medscape Medical News sounded a cautionary note about the petition submitted to the FDA about revising opioid labels.

“I share the concern of this group,” said Charles Argoff, MD, a professor in the neurology department at Albany Medical College and director of the Comprehensive Pain Program at Albany Medical Center in New York. “However, we need to establish prospectively whether this approach accomplishes what this petition suggests it would. This group has yet to prove that the recommendations in the petition are appropriate recommendations.”

Any changes to opioid labeling must be anchored “in the highest-quality medical evidence,” said Dr. Argoff, a member of the editorial advisory board for Medscape Neurology. Otherwise, patients could suffer harm.

“We have a prescription drug abuse crisis…that we must combat,” he said. “But [the petition] does not address the millions and millions of people who have been appropriately prescribed this medication, who have been appropriately monitored, and who have lived a more functional life as a consequence. We need to ensure the availability of these drugs for patients who can benefit from them and establish concrete approaches to limiting the abuses and misuses.”

Dr. Argoff has spoken out in the past on the problem of “allowing physicians with insufficient training to prescribe medications that can kill people.” He reiterated that concern in his remarks on the opioid-labeling petition.

“To demonize the drug is ignoring the responsibility of the prescriber,” he said. (Robert Lowes)

• Neurostimulation
• Targeted Drug Delivery
• MRI Labeling

Neurostimulation

Medtronic is continually advancing neurostimulation therapy with the latest technology.

AdaptiveStim™, exclusively available with RestoreSensor™, is a first-of-its-kind neurostimulation system that uses an accelerometer similar to what is used in smart phones and gaming devices to detect a change in position.

Only AdaptiveStim lets your patient go about their day without using their programmer to change stimulation settings.

It:

• Listens and senses when your patient changes position
• Learns from previous experience and remembers your patient’s last comfortable setting
• Responds and automatically adjusts stimulation to your patient’s optimal setting
• Records your patient’s objective data

Common uses for neurostimulation

• Post-laminectomy pain
• Failed back surgery syndrome
• Degenerative disc disease
• Herniated disc pain
• Complex regional pain syndrome
• Epidural fibrosis
• Arachnoiditis
• Peripheral causalgia

Benefits of neurostimulation

• An effective method of pain control for many patients when used as directed
• May reduce the consumption of oral pain medications
• Reversible—can be discontinued or, if desired by the patient, surgically removed
• Systems can be reprogrammed without surgery
• Patient can control the level of therapy within programmable limits
• Trial of therapy may help assess patient response

Screening test

A screening test provides an opportunity to assess the effectiveness of neurostimulation and gauge patient response without a long-term commitment. The trial offers an adjustment period and time to explore therapy parameters.

The goal of neurostimulation is at least a 50% reduction in pain. However, patient-specific goals may include less pain reduction but improved quality of life.

Risks associated with the use of neurostimulation

Neurostimulation may be associated with adverse events, and each person’s experience may vary. Surgical risks include infection, pain at the implant site, and bleeding into the epidural space. Device risks include corrective surgery, jolting or shocking, lead fracture, lead migration, or lead dislodgement, which may result in unfavorable stimulation or loss of therapy effect.

Targeted Drug Delivery

Potential applications for Targeted Drug Delivery

Since the first implantable drug pump was approved for the treatment of chronic pain more than 20 years ago, Medtronic Targeted Drug Delivery has been used to manage chronic pain in thousands of patients with conditions that include:

• Cancer pain
• Failed Back Surgery Syndrome (FBSS)
• Complex Regional Pain Syndrome (CRPS)
• Compression fractures from osteoporosis
• Postherpetic neuralgia
• Arachnoiditis
• Chronic pancreatitis
• Phantom limb pain

Benefits of Targeted Drug Delivery

Many people experience improvements in their pain symptoms and quality of life after receiving Medtronic Targeted Drug Delivery. Benefits may include:

• Significant (50 percent or greater) reduction in pain^12-14
• Improved ability to function and participate in activities of daily living^13,14
• Lower medication doses compared with oral medications, which may result in reduced side effects^4,6-10
• Fewer oral pain medication(s)^13,14
• Proven safe and effective when used as directed
• Reversible – therapy can be turned off as desired or surgically removed at any time
• Ability to undergo full-body MRI scans – FDA-approved for full-body scans; designed to resume programmed therapy after the scan
• The use of myPTM^®, which provides the patient with the ability to administer medication and maintain control over their therapy
• SynchroMed II is the most tested and experienced drug delivery system, offering unmatched:
  • Reliability, demonstrating 98 percent event-free therapy 48 months in more than 150,000 patients
  • Accuracy, with only 1 percent average flow-rate error in the clinical setting
  • Precision, as the only programmable drug delivery system with 99.7 percent repeatability from pump to pump

Screening test

A screening test is required to assess the effectiveness of Targeted Drug Delivery as a treatment option for chronic pain.

A trial can be performed using various delivery methods:

• Continuous epidural
• Continuous intrathecal
• Bolus epidural
• Bolus intrathecal

Patients who report at least a 50% reduction in pain may be candidates for long-term therapy.

Risks associated with the use of Targeted Drug Delivery

The implanted pump and catheter are surgically placed under the skin. Surgical complications are possible and include infection, spinal fluid leak, and headache. Patients should not undergo the implant procedure if they have an active infection at the time scheduled for implant.

Once the infusion system is implanted, device complications may occur which may require surgery to resolve. Drug overdose or underdose can result because of these complications and have serious and even life-threatening adverse effects. Possible complications include the catheter or pump moving within the body or wearing through the skin. The catheter could leak, tear, kink, or become disconnected. The pump could stop because the battery has run out or because of failure of another part of the infusion system. Additionally, inflammatory mass has been reported at the tip of the catheter, which may lead to complications, including paralysis.

For additional safety information, please refer to the labeling provided with the device and the Important Safety Information at www.medtronic.com/chronicpain. Also it is recommended that patients discuss the benefits and risks of this therapy with their doctor.

MRI Labeling

Nearly 7 million head scans are performed each year in the US—1 every 4.6 seconds.

• Only Medtronic premium neurostimulators have FDA approved labeling for 1.5-Tesla MRI head scan
• Medtronic SynchroMed^® pumps have FDA approved labeling for 3.0-Tesla MRI full body scan

MRI procedures by anatomy

MRI head scans can diagnose several common conditions, including

• Stroke
• Brain tumor
• Cause of headache
• Multiple sclerosis
• Seizure
• Hearing loss

References

1. Medtronic Neurostimulation Therapy for Chronic Pain: Percutaneous Lead Implantation Guide. Minneapolis, MN: Medtronic, Inc.; 2008.
2. Medtronic Implantable Systems Performance Registry (ISPR) 2007 Annual Report: Protocol NSP0010-10000. Minneapolis, MN: Medtronic, Inc.; October 2008.
3. Medtronic Neurostimulation Systems for Pain Therapy Brief Summary. Minneapolis, MN: Medtronic, Inc.; February 2009.
4. Medtronic web site. Link: http://www.medtronic.com/patients/chronic-pain/device/drug-pumps/questions-answers/index.htm. Accessed: February 23, 2012.
5. Brogan SE. Intrathecal therapy for the management of cancer pain. Curr Pain Headache Rep. 2006;10:254-259.
6. Gerber HR. Intrathecal morphine for chronic benign pain. Best Pract Res Clin Anaesthesiol. 2003;17:429-442.
7. Nance P, Meythaler J. Intrathecal drug therapy. Phys Med Rehabil Clin N Am. 1999;10:385-401,viii-ix.
8. Ruan X. Drug-related side effects of long-term intrathecal morphine therapy. Pain Physician. 2007;10:357-366.
9. Smith TJ, Swainey C, Coyne PJ. Pain management including intrathecal pumps. Curr Pain Headache Rep. 2005;9:243-248.
10. Winkelmuller M, Winkelmuller W. Long-term effects of continuous intrathecal opioid treatment of chronic pain of nonmalignant etiology. J Neurosurg. 1996;85:458-467.
11. Onofrio BM, Yaksh TL. Long-term pain relief produced by intrathecal infusion in 53 patients. J Neurosurg. 1990;72:200-209.
12. Doleys DM, Brown JL, Ness T. Multidimensional outcomes analysis of intrathecal, oral opioid and behavioral functional restoration therapy for failed back surgery syndrome: a retrospective study with 4 years’ follow-up. Neuromodulation. 2006;9:270-283.
13. Deer T, Chapple I, Classen A, et al. Intrathecal drug delivery for treatment of chronic low back pain: report from the National Outcomes Registry for Low Back Pain. Pain Med. 2004;5:6-13.
14. Roberts LJ, Finch PM, Goucke CR, Price LM. Outcome of intrathecal opioids in chronic non-cancer pain. Eur J Pain. 2001;5:353-361.