Access to the PPM Journal and newsletters is FREE for clinicians.
13 Articles in Volume 12, Issue #11
“Doc” Holliday: A Story of Tuberculosis, Pain, and Self-medication in the Wild West
"Doc's" Woman: Doc Holliday's Wife
Activation of Latent Lyme Disease Following Epidural Steroid Injection: Case Challenge
An Overview of Complex Regional Pain Syndrome and its Management
Extracorporeal Shock Wave Therapy: Applications in Tendon-related Injuries
Mission Impossible—Developing a Program to Help Chronic Pain Patients
New Ideas for Helping Difficult Pain Patients
Postoperative Pain Relief After Knee and Hip Replacement: A Review
Using Dynamic MRI to Diagnose Neck Pain: The Importance of Positional Cervical Cord Compression (PC3)
December 2012 Pain Research Updates
Best Practices For High-dose Opioid Prescribing
Does Sulindac Affect Renal Function Less Than Other NSAIDs?
The Bewildering Terminology of Genetic Testing

New Ideas for Helping Difficult Pain Patients

Prescribing opioid medication in conjunction with Suboxone may help reduce overall opioid dosages and increase pain control in opioid-tolerant patients.

Most pain practitioners have a few patients who use up their pain medication more quickly than expected. They often claim their medication is just not enough to cover their level of pain. When questioned carefully, the patients note that they run out of pain medicine before their due date, regularly watch and wait for the clock to take their next dose, maybe feel some element of withdrawal before their next dose, and rarely get good pain relief from whatever level of medication that is prescribed. Pain management physicians are taught that these behaviors may represent pseudo-addiction, a drug-seeking behavior that simulates addiction behavior but represents instead that the level of prescribed medication is insufficient.

In September 2008, I attended the yearly conference of the American Academy of Pain Management and listened to Linda Watkins, PhD, lecture on the role glial cells play in attenuating pain.1 She described the basic science and research that showed how glial cells can be responsible for sending pain messages—both in response to injury and in response to prescribed opioid pain medication. Indeed, she noted that the very drugs we prescribed to influence µ receptors and reduce pain sensations also activated glial cells to increase pain. Although I have not seen this in my practice, this phenomenon—hyperalgesia—may underlie the paradoxical response some chronic pain patients experience with high doses of opioids, which seem to increase their pain.

One of the effects of chronic opioid exposure is an excitatory effect on the µ receptor, which contributes to opioid tolerance and opioid-induced hyperalgesia.2 Work by Horvath et al demonstrated that inhibition of micro- glial receptors attenuated morphine tolerance.3 Shen et al showed in a mice retinal lesion model that naloxone modulated microglia accumulation and activation.4

There are two prescription medications commercially available that mute the glial response to pain. These are naloxone, which is used to reverse opioid overdose, and naltrexone, which is approved for the management of alcohol and opioid dependence. Both medications block the µ receptor response to opioids. If taken orally, these agents can also block µ receptor opioid-induced constipation.

In a 2008 animal study, Largent-Milnes et al5 demonstrated that ultra–low dose naltrexone enhanced the effects of both intrathecal and oral oxycodone in the treatment of neuropathic pain caused by spinal nerve ligation. Hutchinson et al demonstrated that the toll-like receptor 4 (TLR4) is a key receptor for initiating microglial activation and maintaining neuropathic pain.6 In addition, the study suggested that TLR4 antagonists, naloxone and naltrexone, can prevent and reverse neuropathic pain. They concluded that naloxone “may be useful clinically to suppress glial activation, and suppress pain.”

Trial of Low-dose Naloxone
In 2008, with the assistance of my compounding pharmacist, I began to prescribe low-dose naloxone or naltrexone in combination with low-dose opioids to approximately 20 of my chronic pain patients who were not getting sufficient relief from their higher-dose opioid prescriptions. The idea was to pretreat the neuronal glial receptors prior to administration of the opioid. Based on the pharmacokinetics of these medicines, the naloxone or naltrexone was administered 60 to 90 minutes prior to the opioid dose. Naltrexone was administered orally, and naloxone was administered sublingually (SL). We quickly learned that naloxone worked better than naltrexone, and administration in this fashion enhanced the pain relief from oxycodone, morphine, hydromorphone, and hydrocodone in some of these patients.

This novel treatment approach helped about 20% of the chronic pain patients in the trial by increasing opioid efficacy and lengthening the time of efficacy from a single dose. The protocol that worked best was 2 mg of naloxone SL, taken 60 to 90 minutes prior to 5 to 10 mg oxycodone/APAP, 10 mg hydrocodone/APAP, 15 mg morphine (either sustained release or immediate [IR]), 10 mg oxycodone, or 5 to 10 mg hydromorphone (extended release or IR). The trial patients who benefited from pretreatment enjoyed increased opioid efficacy with regard to strength and length of time for pain relief after dose. Unfortunately, approximately 80% of the patients did not respond, and the naloxone made no difference either way in their opioid efficacy. Others found the medication too expensive and not covered by their insurance. None suffered a significant side effect, and a few continued the treatment regimen.

In 2007, Richard Gracer published A New Prescription for Addiction. In this book, Dr. Gracer outlined what was known about addiction and tolerance to opioids, and why buprenorphine and naloxone (Suboxone) might work for treating pain.7 While many chronic pain patients can take opioids successfully for relief of pain, others sustain opioid-induced damage to their central nervous system receptors (central sensitization). This damage leads to post acute withdrawal symptoms and opioid tolerance with decreased efficacy with respect to pain relief. Among other effects, opioids stimulate γ-aminobutyric acid (GABA) receptors and eventually this deprives the brain of its ability to feel good without this outside opioid stimulation. Central opioid receptors become less sensitive, and actually change physically and decrease in number. As this occurs, the usual ability of a drug to cause reduction of anxiety is greatly diminished; dopamine levels become low; and agitation, anxiety, and depression set in.

Dr. Gracer describes this phenomenon in terms of what we know about opioids that activate GABA receptors, and the effects of dopamine and glutamate. In these patients, altered receptors and receptor sites must be addressed by an increase in medication dose to reduce cravings before the medication can provide pain relief. In other words, the spill over of opioids after filling receptors that cause craving is used by the body for pain relief. Gracer theorized that with increased receptor damage, less of the opioid dose can be used for pain relief because the receptors that satisfy craving must be filled first.

Another factor influencing pain relief from opioids is the effect of these medications on κ receptors. While the µ receptor system causes relaxation, pleasure, and pain relief, the κ receptors cause excitement, irritability, and anxiety. Opioid medications stimulate µ receptors and block the action of the κ system. Buprenorphine (a partial µ opioid agonist) is a medication that has potent κ opioid receptor antagonist activity.8

This information and a conversation with Dr. Gracer led me to conduct an informal clinical trial prescribing Suboxone, which contains both buprenorphine and naloxone, instead of naloxone alone. Suboxone is approved by the FDA for the treatment of opioid dependence. The protocol for this trial was the same as the naloxone trial, with patients taking Suboxone (8/2; 8 mg buprenorphine, 2 mg naloxone) 60 to 90 minutes prior to the low dose of opioid medication as described above. With the efficacy of buprenorphine as a κ antagonist in combination with naloxone, the entire cohort of patients who tolerated Suboxone responded positively. There were no significant side effects, and pain relief was impressive. Those who discontinued the protocol suffered nausea with Suboxone, or found the medication too expensive (around $600 per month without insurance).

In the past few years of using this protocol, some patients have elected to decrease their Suboxone dose to reduce the cost that their insurance programs charged. Some have been able to successfully use one-quarter to one-half of Suboxone 8/2 in the same sequence and with similar efficacy for pain relief. Other patients have been treated effectively taking the sequence of Suboxone/opioid every 12 hours. In general, these patients have not been able to discontinue either the Suboxone or the opioid without a return of their previous problems.

In summary, the efficacy of this protocol for difficult opioid-tolerant patients continues to be impressive. Some of these patients have been followed for 3 years with no significant side effects or change in efficacy with regard to pain relief. We currently have approximately 25 patients using this treatment protocol successfully. No patients have discontinued the treatment, other than those forced to by economic factors beyond their control. While it is unorthodox, it represents safe, efficacious, and legitimate off-label prescribing for a very difficult-to-manage cohort of pain patients. In today’s climate of patients dying from high doses of opioids, this protocol enables doctors to use lower and safer doses while achieving dramatically improved results.

Last updated on: December 20, 2012
close X