Research published at International Conference on Opioids, Harvard Medical School, Boston, Massachusetts

Research published at International Conference on Opioids, Harvard Medical School, Boston, Massachusetts

 
Below is a summary of our research presented June 09-11, 2013, at the Third Annual International Conference on Opioids, Harvard Medical School, Joseph P. Martin Conference Center, Boston, Massachusetts. This study was done jointly by Dr. Damiani and Dr. Campa.

Dr. Campa was on-site to present our findings. We believe our research will help other physicians treat more safely those patients who present with persistent pain, requiring high dose and/or prolonged use of narcotics.

John A. Campa III, MD
Clinical Neurosciences
June 18, 2013

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Correlation Of Oxycodone Daily Use To Oral Fluid Levels And Its Potential For Detection Of Opioid Induced Hyperalgesia 
- A Pilot Study

L. Damiani, PhD, MD-Candidate, School of Medicine, University of New Mexico, Albuquerque, NM; J. A. Campa III, MD, Albuquerque, NM; Faculty, School of Medicine, University of New Mexico, Albuquerque, NM.

Background

Clinicians who treat patients suffering from persistent pain must face the issue of monitoring and regulating opioid medication consumption. Evidence suggests prolonged exposure to opioids may lead to Opioid Induced Hyperalgesia (OIH), i.e., the patient becomes paradoxically more sensitive to pain². Hence, an easily performed lab assay, i.e., oral fluids toxicology (OFT), would be an invaluable clinical tool to assist the clinician in providing safe opioid dosing, while avoiding the induction of OIH.

Aim

The aim of this study is to assess the reliability of the oxycodone OFT therapeutic range and its potential for detecting risk for OIH.

Methods

A 10 month retrospective chart review was performed to study patient oxycodone use and its measurement by OFT (Forensic Fluids Laboratories, Inc, Kalamazoo, MI).

Hypothesized OIH Thresholds

We believe the hypothesized daily opioid amount in morphine sulfate equivalents (MSEq), where OIH is likely present, is 300 mg per day. Similarly, the hypothesized daily amount where a patient is at probable risk for OIH induction is 86.5% of 300 mg or 260 mg (MSEq). The rationale for these thresholds is based on our unpublished clinical observations and experience. The only study done within the last 10 years looking at daily morphine equivalents intake and OIH has set a range at approximately 90-200 mg/day⁶. Therefore, a better understanding of the range for morphine equivalents and OIH is required. The oxycodone MSEq is calculated by multiplying the daily amount in milligrams by 1.5. Inclusion criteria: patients taking oxycodone who had OFT.

Results

A total of 19 patients were eligible for the study. Probable OIH was postulated in four patients (P6, P7, P15, P19) and two were deemed to be at risk for OIH (P8, P16). Of the remaining 13/19 (68%) patients not at risk for or having OIH, our data reveals that OFT reliably assessed oxycodone use, relative to the therapeutic range (10-500 ng/ml), in 85% (11/13) of patients (outliers, P5, P9). Of the remaining six with abnormal results > 500 ng/ml, two of the four patients with probable OIH (P6, P15) and one of the two at risk for OIH (P16) were detected, for a reliability detection rate of 50%.

Discussion

The aim of this study was to assess the reliability of the OFT lab’s oxycodone therapeutic range and its potential for detecting risk for OIH, i.e., would it correspond to what we perceive as excessive use of oxycodone, resulting in OIH. The discrepancies between our patients perceived to be overusing oxycodone and the results returned by the lab are likely a function of at least three factors: 1. how the therapeutic range was determined, 2. high metabolizers, 3. patient non-compliance.

According to Wylie et al.⁵, the ability to detect drugs in oral fluids was based upon saliva specimens collected from a drug-free, healthy population, which were then “spiked” with varying drug concentrations. No population-based study was done to determine actual therapeutic levels. The therapeutic ranges were determined from an article stating, “we have gathered the data in the table from the literature and from personal experience. These values are not considered absolute, but are to be used as a guide in evaluating a given case. The values can be affected by dose, route of administration, absorption differences, age and sex, tolerance, method of analysis, pathological or disease state, postmortem redistribution, etc.” ⁹ Therefore, although the therapeutic range set by the lab is not necessarily inaccurate, our results demonstrate that a new therapeutic range for oxycodone may be needed, as some patients with or at risk for OIH were not detected with the lab’s current reference range.

Regarding high metabolizers, the one patient who was at risk for developing OIH (P8), that remained undetected by OFT, was a smoker. Alternatively, those that remained undetected by OFT, may have simply been non-compliant, i.e., taking less medication than admitted to. Hence, the clinician must consider the potential for nicotine related (and other agents) induction of the hepatic microsomal enzyme system and non-compliance when assessing patients undergoing OFT.

Opioid Induced Pseudoneuropathy - OIP?

An unexpected finding at six weeks after patient P6 was completely withdrawn from all opioids, was his regained ability to play the saxophone after 15-20 years. He had previously been told his inability to feel the key pads on the instrument was due to his underlying and progressive neuropathy. His improved touch sensation and ability to now actually play the instrument may be explained by an additional peripheral nerve impairment induced by the high dose of opioid and/or extended exposure period for which he had been on opioids. This certainly requires more in depth study, as an underlying new iatrogenic entity may have been responsible, i.e., opioid induced pseudoneuropathy.

One way to study this problem would be to perform serial electromyography and nerve conduction velocity studies every six months, as the opioid dose is increased and OIH symptoms begin to appear. Of course, a baseline study would be crucial to quantify the degree of any opioid induced delay in nerve conduction, whether it be in the peripheral nerve itself or at the receptor level.

Screening Questionnaire

Development of a questionnaire would be a very helpful tool to screen for patients with or at risk for OIH – as it is likely that we do not completely know what the best lab and clinical therapeutic ranges are for patients taking oxycodone. One patient in this study, P15, who we thought would meet our OIH criteria, as this person did exhibit symptoms of OIH, remained outside the detection threshold (225 mg morphine equivalents per day). Hence, given the purported neurophysiopathology leading to OIH, one clinical value that should be considered is the pain score.

For this discussion, drug tolerance or tolerance to a narcotic analgesic is said to exist when greater and greater doses and/or strengths of the medication are needed to achieve the same desired effect (i.e., pain relief).¹⁰ This typically occurs within 3-6 weeks of a dose change, and there will always be a period of time after the dose is increased where pain control is deemed adequate by the patient. This is in stark contradistinction to OIH, where an increase in dose is not accompanied by any period of adequate pain relief and there is a concomitant and definite increase in pain. Suggested survey questions are outlined below, however, it is assumed that a progression of the patient's underlying pathology has been ruled-out before considering OIH or drug tolerance.

Model Questionnaire

1) On a scale of 0-10, where zero is no pain, and 10 is the worst pain imaginable, what is your average pain score over a week’s time?

- Establishes baseline score for future comparisons.

2) Is this pain score better or worse than on your last visit?

- If better, OIH not likely.

- Underlying pathology improving?

- If worse, then OIH a possibility, but drug Tolerance must also be considered.

3) Is your pain getting worse before you take your medication?

- OIH and Tolerance possible, but also End of Dose failure must be considered, due to inadequate dose or dosing interval.

4) If your pain is getting worse, does the same dose of pain medication still work?

- If no, then OIH and/or Tolerance must be considered.

- Pathology progressing?

5) Is the pain better or worse since your last dose increase?

- If worse, then OIH may be present. See #6 below.

6) If pain worse, when was your last dose increase?

- If less than 1-4 weeks à OIH likely present.

- Otherwise, then Tolerance may have developed.

Conclusions

We conclude that OFT and its current therapeutic range reliably detects when an excessive amount of oxycodone is taken in most patients (85%). However, for patients at risk for or likely having OIH, this detection rate drops to 50%.

Hence, further study is needed to refine the current oxycodone therapeutic range and OIH thresholds to improve detection efficiency. Additionally, these data suggest patients consuming ≥ 260 mg. MSEq of oxycodone per day are at risk for having or developing OIH.

References

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3. Celerier E, Laulin JP, Corcuff JB, Le Moal M, Simonnet G. Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: A sensitization process. J Neurosci. 2001;21(11):4074-4080.

4. Carroll IR, Angst MS, Clark JD. Management of perioperative pain in patients chronically consuming Oxycodone. Reg Anesth Pain Med. 2004;29(6):576-591.

5. Wylie FM, Torrance H, Anderson RA, Oliver JS. Drugs in oral fluid part I. validation of an analytical procedure for licit and illicit drugs in oral fluid. Forensic Sci Int. 2005;150(2-3):191-198.

6. Mercadante S, Ferrera P, Villari P, Arcuri E. Hyperalgesia: An emerging iatrogenic syndrome. J Pain Symptom Manage. 2003;26(2):769-775.

7. Guignard B, Bossard AE, Coste C, et al. Acute Oxycodone tolerance: Intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology. 2000;93(2):409-417.

8. Fabregat-Cid G, Asensio-Samper JM, Villanueva-Perez V, Lopez-Alarcon MD, De Andres-Ibanez J. Postoperative pain management for patients who are long-term users of Oxycodone. Rev Esp Anestesiol Reanim. 2011;58(1):25-33.

9. Winek CL, Wahba WW, Winek CL, Jr, Balzer TW. Drug and chemical blood-level data 2001. Forensic Sci Int. 2001;122(2-3):107-123.

10. Campa JA. Narcotic Analgesics – A Reference For the Clinician. San Antonio, TX.: Legacy Publishing SA; 2006.