There is no shortage of guidelines for opioid use in chronic noncancer pain.1-4 All of them advocate in some form that clinicians use universal precautions that include urine drug testing (UDT), controlled substance agreements (CSA), and in most cases incorporate validated risk stratification tools prior to and during opioid therapy. All attempt a definition at what constitutes “high dose” morphine equivalents and what that means in terms of risk, but few agree on a standard opioid conversion (good topic for another blog).
Clinicians sometimes avoid UDTs and CSAs because it is uncomfortable broaching the topic with long term patients and/or they don’t want to jeopardize the patient-provider relationship or alienate their patients. The issue reaches a whole different level when I approach the topic with oncologists, palliative care, and hospice providers. The sad truth is that cancer should not be a free pass to substance diversion; that’s not to say that it is a huge problem, but clearly it has never been quantified and without a doubt, just because a patient or family member develops cancer, it does not cancel out a previous history of substance abuse. There is after all a subset of substance abusers that do develop cancer, just like any other disease (also a topic for another blog…stay tuned).
In my experience, honest patients generally have no problem participating in various testing or signed agreements when it is carefully explained that all patients are treated equally and that there is an unfortunate public health risk and liability to providers. Certainly when given the choice of the “pharmacy crawl” or acquiescing to appropriate tests, most good patients would happily select the latter.
SERUM TESTING (START YOUR ENGINES)
No guidelines require or suggest that serum opioid testing is useful or should be a standard of care. In this blog, I intend to explain why this could be useful and I hope to dispel certain myths on the topic, will wrap up with a couple of cases, and encourage input from my esteemed colleagues and patient followers.
Before making my case however, Pharmacy Pain and Palliative Care PGY2 Resident Dr. Tim Atkinson helped scour the literature to prove that there is limited evidence. Why you might ask? (Keep your foot on the clutch for now)
PubMed was searched using blood levels + opioid monitoring yielding 145 results. All studies mentioning opioids were reviewed for inclusion or excluded if they focused on anesthesia, behavorial monitoring, or dose increases without measuring blood levels. Most studies included describe various testing technologies (LC-MS/MS vs GC-MS), post-mortem and antemortem concentration correlation, and methadone serum monitoring. The only articles mentioning serum monitoring were regarding methadone treatment programs focusing on compliance and attempting to correlate doses with levels and predict the effect of various drug interactions.
A linear dose-response can be predicted according to Gergov and colleagues.5 It appears that when they attempted to use a quadratic regression it only correlated well with the highest concentrations perhaps even toxic. They ended up diluted those higher samples and correlating them with linear reference standards further reinforcing utilization. In addition, among other challenges they list blood thickening as a problem with using post-mortem samples which obviously won’t be a problem for our patients.
There are at least four reasons to monitor serum opioid levels:
- Some patients will have lower or higher than expected serum levels due to polymorphic variations.
- Some patients will have lower or higher than expected levels due to significant drug interactions.
- Elevated or diminished serum levels could help guide the clinician to select a drug dose for opioid rotation and prevent overdose or underdose (withdrawal). Consider a referred patient on fentanyl 100mcg/hour patch requiring conversion to OxyContin. If the patient is either not using the fentanyl, or not absorbing the fentanyl, a conversion to OxyContin could result in death.
- Some patients may be taking part or none of their medications…this is a public safety risk in the case of diversion, a significant cost to society, and just plain problematic on many levels. UDTs do not quantify or predict ingested dose.
The first two above are very important therapeutic issues that could help clinicians to better understand why a patient isn’t responding to therapy or why a patient has toxic side effects that might otherwise be misinterpreted as overuse or misuse by the patient. This could be a natural progression to pharmacogenomic testing or at least switching to an opioid with a differing metabolic pathway.
Who will pay for this and who is inconvenienced?
These are questions I am often asked. First, patients must understand that it is at least as inconvenient for the prescriber to order and interpret the tests as it is for the patient to have blood drawn. We don’t want to do this anymore than the patient wants it done. Third party payment for serum monitoring is really a “no brainer” and requires education to the payers. Many years ago I approached certain laboratory folks and administrators about serum testing, but nobody wanted to pay for the tests. Once I “showed them the money” it became quite clear that serum testing was worth every penny. Not doing it may be penny wise and pound foolish.
By way of example, a prescription for #60 OxyContin 60mg costs approximately $747.00 at CVS in upstate NY which is a one month supply assuming a dose of OxyContin 60mg every 12 hours. A one year supply for a single patient costs $8964.00 per year. An oxycodone serum test using liquid chromatography–tandem mass spectrometry costs $134.00 in upstate NY (price will be lower on contract). The yearly cost for two tests would be $268.00.
If 50 patients received the dose above, OxyContin over one year = $448,200
Two tests per year for each patient (100 tests total) = $13,400
If 4% (2 out of 50 patients) were not taking their OxyContin, the savings in one year for discontinuing therapy = $17,928. For just two non-compliant patients, the net gain to third party payers is $4528 per year for testing all 50 patients twice yearly. Believe me, 4% is probably a fraction of the actual percentage, and the net profit could help to offset serum testing for less expensive extended release products such as morphine and also methadone (which of course is not extended release).
- Last year, my colleagues and I reported a case of low serum morphine 6 in a patient that was 75% less than expected by calculation. The patient had a history of infectious endocarditis and was being treated with rifampin. As most of you know, since morphine does not engage in cytochrome P450 metabolism, we wouldn’t expect an interaction. But, since rifampin is a potent p-glycoprotein inducer, morphine absorption was severely impacted by stimulating the gastric efflux pump and preventing absorption. 6 (If requested, you may qualify for a copy) This concept was hit home with a subsequent publication in an even more frightening interaction with methadone and telaprevir.7 Imagine if this patient had been tested in a clinic with a previous history of heroin abuse and his serum levels were 75% less than predicted…he would have been falsely accused of selling his morphine. That’s why any test, UDTs or serums, require a keen knowledge of how to interpret unexpected results. And how about this? What happens when the rifampin therapy is complete and the serrum morphne levels jump by 75%?
- In a second case, a patient was receiving oxycodone as follows: OxyContin 80mg PO q12h; OxyContin 20mg PO q8h; oxycodone IR 10mg PO q4h. Pt uses #240 per month. The UDT for opiates is negative. Quantitative urine confirmation for oxycodone yielded a value of 438ng/mL. A follow-up serum was reported at 19ng/mL, a level consistent with a daily oxycodone dose of perhaps 30mg per day (but prescribed daily dose was 280mg per day). “Dose proportionality and/or bioavailability has been well established for 10mg, 20mg, 40mg, 80mg, and 160mg tablets strengths for both peak plasma levels (Cmax) and extent of absorption (area under the curve). At a dose of 10mg sustained release oxycodone PO q12h, the mean maximum serum concentrations (+/- SD) for sustained release oxycodone has been reported as 15.1 +/- 4.7 ng/mL”. We can expect 90% confidence levels with these numbers. (Per OxyContin package insert, Reder RF, Oshlack B, Miotto JB, Benziger DD, Kaiko RF)
This patient is taking no more than 30mg of immediate release oxycodone per day. Street value of the medication balance is over $6000.00 per month, tax free of course!
I think it’s about time something is done to validate opioid serum analysis clinically, educate the opioid prescribing world, and do some prospective studies. Data is in fact available, as seen HERE which has been available on paindr.com for many years. You can be sure that no new opioid or new opioid formulation has been approved in the last several years or has/will come to market without having significant serum pharmacokinetic data. So, yes, we do have the data, but clinicians need to know how and why it is clinically useful and the pitfalls of utilizing such tests. Nobody squawks about serum carbamazepine, valproate, phenytoin, or LFTs for statins.
In patients that are poor methadone metabolizers, someone with a higher than expected methadone level is at higher risk of widened QTc, the side effect of which is death. This may also be problematic in certain patients receiving low dose methadone that have elevated serum levels because of a drug interaction. A good example is the antiretroviral nevirapine; I have seen widened QTc’s in some of these patients, and low and behold, when doing a serum, it is often 4 to 10-fold higher than expected. And we wonder why 30% of all opioid deaths involve methadone? Maybe a significant portion of that is not just polymorphism and poor conversion ratios, but also significant and sometimes unexpected drug interactions as noted above with telaprevir.6
And finally, when a coroner reports cause of death to be “opioid overdose” do to serum levels, it is unconscionable to say such a thing without factoring in for “redistribution”8,time and location of sampling, and the amount of opioid a patient was able to tolerate for the last several days, weeks, or years preceding death.
I would be especially grateful for any input from our pain clinician colleagues here and invite comments from patients as well.
- Manchikanti L, Abdi S, Atluri S et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2-guidance. Pain Physician. 2012; 15(3 suppl):S67-S116.
- Chou R, Fanciullo G, Fine P et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009; 10(2):113-130.
- American Society of Anesthesiologists (ASA) and American Society of Regional Anesthesia and Pain Medicine(ASRAPM). Practice Guidelines for Chronic Pain Management: An Updated Report by the ASA Task Force on Chronic Pain Management and ASRAPM. Washington, DC: ASA & ASRAPM, 2010.
- Model Policy on the Use of Opioid Analgesics in the Treatment of Chronic Pain. 2013. Federation of State Medical Boards. http://www.fsmb.org/pdf/pain_policy_july2013.pdf
- Gergov M, Nokua P, Vuori E, Ojanpera I. Simultaneous screening and quantification of 25 opioid drugs in post-mortem blood and urine by liquid chromatography-tandem mass spectrometry. Forsen Sci Intl. 2009; 186:36-43.
- Fudin J, Fontenelle DV, Payne A. Rifampin Reduces Oral Morphine Absorption; A Case of Transdermal Buprenorphine Selection Based on Morphine Pharmacokinetics. Journal of Pain & Palliative Care Pharmacotherapy. 2012;26:362–367.
- Fudin J, Fontenelle DV, Fudin HR, Carlyn C, Ashley CC, Hinden DA. Potential P-glycoprotein Pharmacokinetic Interaction of Telaprevir with Morphine or Methadone. Journal of Pain and Palliative Care Pharmacotherapy. August 2013, Vol. 27, No. 3, Pages 261-267.
- Cook DS, Braithwaite RA, Hale KA. Estimating antemortem drug concentrations from postmortem blood samples: the influence of postmortem redistribution. J Clin Pathol 2000;53:282–285.