Strategies for Prescribing Opioids Appropriately

Author

Charles Opperman, MD, Sycamore Primary Care, Clinical Teaching Faculty, Kettering Medical Center Internal Medicine Residency, Miamisburg, OH

Peer Reviewer

John Kelly, MD, Neuroscience Associates of Northern Kentucky, Crestview Hills, KY

EXECUTIVE SUMMARY

The epidemics of opioid overdose deaths and heroin use have gained national attention, including debate topics in the 2016 Presidential race. Primary care physicians have been included in the blame due to their perceived knowledge gaps and inappropriate prescribing habits.

• Chronic pain is the most prevalent patient complaint, with nearly 50% of the general population stating that they have some form of chronic pain.
• The basic principles underlying the medication agreements are: 1) medications will be taken only as prescribed and will be prescribed only by one provider; 2) patients agree to be subjected to random drug monitoring and random pill counts; 3) patients are expected to abstain from illegal or “street” drugs; and 4) any breech of the agreement will most likely result in discontinuation of the prescribed controlled substance.
• Data from Prescription Drug Monitoring Programs to identify past and present opioid prescriptions should be accessed at initial assessment and during the monitoring phase.
• Although urine drug screening is the gold standard for monitoring compliance and identifying abuse, it has many limitations and should be supplemented with urine confirmation testing and sampling of other body fluids such as blood.

Prescription opiate abuse and misuse has become a growing epidemic recently, and the problem seems to be propagating without an immediate end in sight. It is known that prescription opiate abuse has clear links to heroin abuse (which also has become increasingly more prevalent), and, in some instances, primary care physicians may be adding fuel to the proverbial fire. By their very nature, physicians tend to be empathetic, caring, and have an overwhelming desire to help alleviate suffering. But when coupled with the malicious behaviors of a drug-seeking patient who is able to tug on those very heartstrings, the inappropriately equipped, well-meaning physician may find himself inadvertently contradicting one of the basic principles of the Hippocratic Oath: First, do no harm.

THE PROBLEM (EPIDEMIC)

According to Centers for Disease Control and Prevention, people who abuse or are dependent on prescription opioid painkillers are 40 times more likely to abuse or be dependent on heroin, leading to the conclusion that the strongest risk factor for a heroin use disorder was a prescription opiate use disorder. Alarmingly, significant increases in heroin use were found in groups with historically low rates of heroin use, including women and people with private insurance and higher incomes.¹ Since the 1970s, when intravenous (IV) heroin use was heavily stigmatized and often feared, heroin has become significantly more pure in quality. Although historically the impurity of the heroin essentially prevented widespread use in alternative forms, such as smoking or snorting, today’s heroin can be abused in a variety of ways to obtain the desired “high.” The link between prescription opioid use and heroin abuse is undeniable and, by sheer number, primary care providers are responsible for the majority of pain medication prescriptions dispensed in the United States.²

In 2012, approximately 8% of 12th graders admitted to abusing prescription opioid painkillers, and of those surveyed, approximately 50% stated that prescription opioids were either “easy” or “fairly easy” to obtain.³ Another study, which surveyed patients with a mean age of 32 years who had been self-admitted for detoxification treatment from heroin, found that 73% started their opiate addiction with some form of prescription opiate (41% from “well-intended” pain medication, 32% from diverted prescription medication). Participants from the study were quoted of saying, “kids are using it like Viagra,” opiates are available “at the prom,” and “the best way to get opiates is to look for the dying person who will give [them] up.”⁴ To shed further light on the vastness of the problem, buprenorphine-naloxone (Suboxone), which is a medication used to treat opioid dependence, far outranked insulin aspart (NovoLog) products in prescription numbers in 2014.⁵ Meanwhile, the total number of prescriptions written for hydrocodone and oxycodone has nearly tripled since 1991.⁶ Hydrocodone prescribing far exceeds oxycodone. One possible explanation for this finding is that prescribers may view hydrocodone as a less addictive medication or less potent than equivalent doses of oxycodone. However, data suggest that the abuse liability profile and relative potency of these two commonly used opioids do not differ substantially.⁷

INTERVIEW WITH A FORMER “DRUG-SEEKER”

To better understand the gravity of the prescription opiate epidemic, the author was fortunate to interview several local law enforcement officers with expertise in narcotics. Through that process, the author was introduced to “John,” a recovering heroin addict who had been “clean” for 2 years prior and was a self-admitted “physician manipulator” who frequently obtained prescription narcotics from physicians for the purposes of abuse or sale. The interviews were particularly enlightening and revealed a side of the prescription opiate issue that is often hidden from the 8-5 office hours of the physician.

Although prescription opiates essentially are indicated for one sole purpose, the reality is that they often are used “off-label.” In a perfect world, the prescriber provides an appropriate amount of narcotic pain-relief medication, which would serve to alleviate the patient’s pain to a tolerable level while promoting functionality, to the completely honest patient who only takes the medication as prescribed. This ideal patient also would participate in narcotic agreements, have appropriate urine drug screens (UDS), and desire alternative therapies to help alleviate his or her pain. Unfortunately, this is not a perfect world and far too often the ideal patient is elusive.

Inappropriate prescription opiate use varies greatly in its severity, ranging from a patient taking his or her medication not as prescribed to a patient selling his or her prescription to provide funding for a heroin addiction. In the author’s local “drug economy,” hydrocodone and oxycodone sell on the street for between $1-2 per milligram, which equates to $1200-2400 for each 120-tablet prescription. In contrast, heroin caps (heroin that is stored in pill capsules) can be purchased for half the price or less. In John’s instance (and likely many others), the prescription opiate would be obtained for free through Medicaid and subsequently sold on the street in exchange for heroin, with the seller netting the difference in cash.⁸

Some speculate that the series of events leading to IV heroin addiction go as follows: Prescription opiate abuse leads to smoking/snorting of heroin (because heroin is cheaper on the street or because the physician stopped prescribing). This leads to IV heroin injection because the user develops tolerance to snorting or smoking the heroin, and IV injection has a more immediate onset of action. While snorting or smoking heroin is certainly not void of adverse medical effects, such as respiratory depression, the transition to injection heroin use becomes fraught with a new set of medical dangers. The risk of overdose also increases with injection use, and an alarming trend in heroin overdose deaths has been witnessed in recent years.⁹

IS CHRONIC OPIOID THERAPY FOR CHRONIC NON-CANCER PAIN INDICATED?

For three decades, there has been hope that more liberal use of opioids would help reduce the number of Americans with unrelieved chronic pain. Instead, it has produced an epidemic of prescription-opioid abuse, overdoses, and deaths — and no demonstrable reduction in the burden of chronic pain.^10,11 A retrospective case study of only 38 patients, published in 1986, is considered the seminal paper triggering widespread adoption of liberalized opioid use. The study showed that nearly 40% of patients prescribed chronic opioids achieved “inadequate relief” from their pain.¹² Often citing the aforementioned study, widespread use of prescription opioids was propagated with the establishment of the “pain as the 5th vital sign campaign” despite the absence of any clear evidence from clinical trials that opioids could be used safely and effectively in patients with chronic non-cancer pain (CNCP).¹³ In the late 1990s and early 2000s, physicians were misled by pharmaceutical companies like Purdue Pharma (manufacturers of OxyContin), who paid for lavish conferences in exotic locations to help promote their drugs, which they falsely claimed had very low addiction potential. In 2007, three company executives from Purdue Pharma pled guilty to criminal charges of misbranding OxyContin by claiming it was “less addictive” than other opioids.¹⁴ In recent years, several of the physicians who originally had championed the widespread liberalization of chronic opioids for CNCP have reversed their positions and even acknowledged that their previous position in the matter was a mistake.¹⁵

The vast majority of data and general consensus among experts would suggest that opioids for pain relief can be safely and effectively used in an acute setting for less than 3 months’ duration.^16,17,18 Data also point to a strong inverse relationship between the age of the patient and the risk for opiate abuse or misuse.¹⁹ In contrast, accumulating evidence supports the increased risk for serious harms associated with long-term opioid therapy (> 3 months), including overdose, opioid abuse, fractures, myocardial infarction, and markers of sexual dysfunction.²⁰ Strong predictors of opioid misuse have been demonstrated in patient populations with self-reported histories of previous alcohol or cocaine abuse, or previous criminal drug- or alcohol-related convictions. Younger age and history of depression also have been linked to opioid misuse.^21,22

Although no standard guidelines or indications for treating chronic pain have been established, prescribers should use this knowledge of opiate misuse tendencies and treat each individual case as an investigation to determine if chronic opioids are warranted. For example, a 91-year-old woman with severe rheumatoid arthritis who takes 5 mg hydrocodone to help her ambulate in the morning will likely have significantly less risk for opiate abuse or misuse. That chronic opioid prescription is probably OK. However, it would still be advisable to perform random urine drug screening, pill counts, etc., to ensure compliance. Additionally, elderly patients have a high risk of having their prescriptions manipulated or stolen by family members or caretakers who are diverting or abusing them — another reason to exercise universal diligence while prescribing opioids. In contrast, prescribers should strongly consider alternative strategies to opioids for helping the 45-year-old male with chronic lumbar degenerative disc disease who also has a history of depression and alcohol abuse. This can be a particularly difficult task. Often, patients are very nice, and often, they truly have severe pain. However, the younger, male patient with history of depression and alcohol abuse presents a much higher risk of life-long addiction, opioid hyperalgesia, and tolerance (to name a few side effects) than does the aforementioned 91-year-old. Prescribing chronic opioids to this patient may be the easier route, and it also may be the patient’s preference, but physicians can quickly find themselves causing unintentional harm from their seemingly benevolent action.

Prescribers should remember that the indication of chronic opioids for CNCP is not black and white. Each decision to treat a patient with chronic opioids should be weighed with heavy scrutiny. Once an opioid is started chronically, the prescriber should have the expectation that it will be extremely difficult, if not impossible, to discontinue. Rather, the prescriber most likely will need to treat the patient with escalating doses of opioids because of tolerance build-up. If the prescriber believes the patient is low-risk for abuse and side effects, but determines that life-long therapy with opioids is likely to improve the patient’s functionality and analgesia, then the prescriber should proceed with the decision to prescribe chronic opioids with a monitoring plan and goals of therapy in place. Special caution should be exercised when initiating opioids in a primary care setting, especially in younger patients with chronic conditions or in patients with minimal objective findings. Subsequently referring them to a pain management specialist creates a difficult scenario, as patients will equate euphoria with analgesia, making it difficult for the specialist to utilize alternative therapies. Patients should be cautioned that being pain-free is not a realistic goal. Opioids should be prescribed at the lowest possible dose to achieve improvement in functionality while maintaining a tolerable, but not pain-free, level of pain.

MONITORING FOR COMPLIANCE

Chronic pain is a particularly challenging diagnosis to adequately treat in the outpatient setting, and yet, it is the most prevalent complaint, with nearly 50% of the general population stating they have some form of chronic pain.²³ Recently The Joint Commission, publishers of the Pain as the 5th Vital Sign initiative, released an updated “clarification of the pain management standard.” Within this recommendation, nonpharmacologic strategies such as physical modalities (acupuncture, chiropractic, osteopathic manipulation therapy, massage therapy, and physical therapy) prior to pharmacologic strategies are encouraged in the treatment of chronic pain. Within the pharmacologic strategies for treatment of chronic pain, non-
opioid medications are listed for consideration prior to the opioids.²⁴ The general consensus is to reserve opioids in the treatment of nociceptive pain until after nearly all other modalities have been tried and failed.²⁵ (See Figure 1.) For treatment of chronic neuropathic pain, again opioids are typically reserved until after other modalities have been tried and failed.^26,27 Even if various treatment strategies fail, health care providers are not obligated to use opioids when a favorable risk-benefit balance cannot be documented. If opioids are started, they should be started at the lowest effective dose with specific goals of treatment in place and an appropriate discontinuation and tapering plan²⁸ (although, realistically, the latter may prove to be too optimistic).

FIGURE 1. NOCICEPTIVE PAIN ALGORITHM

Once the physician and the patient have discussed long-term opioid therapy, including side effects, risk of addiction, and risk of tolerance requiring escalating dosing, among other considerations, the patient and physician should preferably enter into a signed agreement. There are many variations of these medication agreements readily available through an Internet query. The basic principles underlying the medication agreements are: 1) medications will be taken only as prescribed and will be prescribed only by one provider; 2) patients agree to be subjected to random drug monitoring and random pill counts; 3) patients are expected to abstain from illegal or “street” drugs; and 4) any breech of the agreement will most likely result in discontinuation of the prescribed controlled substance. Individual agreements vary and many have extensive provisions in place to reduce misuse and abuse.

After the signed agreement is in place, all patients should be screened with urine toxicology prior to initiation of controlled substances. Obviously, aberrant findings on urine testing should prompt very strong reconsideration for prescription of chronic opioids. However, the physician should always exercise caution when interpreting these results, as most urine drug screens have high sensitivity at the expense of their specificity. Interestingly, quinolones, such as ciprofloxacin or levofloxacin, often can cause false-positive opioid results.²⁹ False-positive results for amphetamines also are particularly common, and hence, all positive findings should be sent for further confirmation, often with gas chromatography/mass spectroscopy (GC/MS).³⁰ (See Table 1.)

Finally, data from Prescription Drug Monitoring Programs (PDMPs) to identify past and present opioid prescriptions at initial assessment and during the monitoring phase should be accessed.²⁸ These PDMPs allow state agencies to better identify individuals (patients or providers) and pharmacies who divert controlled substances, and allow for evaluation of prescribing trends.³¹ PDMPs continue to be among the most promising state-level interventions to improve painkiller prescribing, inform clinical practice, and protect patients at risk. Forty-nine U.S. states (excluding Missouri) currently have active PDMPs that physicians can access. Sen. Rob Schaaf (R-Mo.), also a family physician, has opposed legislation to enact a PDMP in Missouri secondary to his belief that it imposes on privacy. In contrast, Ohio recently updated its requirements for opioid prescription so that the physician must query the PDMP at least every 90 days to remain in compliance with the law regarding opioid prescribing.³² Nonetheless, the majority of practicing physicians in the United States have access to a PDMP and should refer to it frequently when prescribing opioids.

URINE DRUG SCREENING AND THE COMMON PITFALLS

In addition to the previously mentioned risk of obtaining a false-positive result, point-of-care (POC) urine drug screening can present a slew of issues that complicate decision-making rather than providing valuable information to improve clarity. Many problems can arise from misinterpretation of the UDS, including accusations of inappropriate drug use, increased cost for follow-up care, denial of medication, denial of insurance or reimbursement, expulsion from pain management programs, and social consequences such as parental or work-related costs.³³ One of the most common pitfalls that I have observed from working with the residency clinic is the failure to document the patient’s last ingestion time of any substances that could affect UDS results. The crucial question that always must be answered is: What should the results of the urine drug screen demonstrate? Failure to preemptively know the answer to this question makes interpretation of the UDS essentially impossible.

As an example, if a patient ran out of his or her prescription for hydrocodone, he or she needs to inform the prescriber. Typically, if that ingestion occurred within the previous 48 hours, the POC urine drug screen should flag positive. Alternatively, if the patient last ingested the hydrocodone > 48 hours prior to testing, the screening will generally be negative for opiates. However, one must again demonstrate caution with interpretation of these results because many factors, such as patient age, weight, gender, metabolism, genetics, cutoff limits for sensitivity, amount of ingestion, chronicity of use, and collection of sample, will alter the detection times within the urine sample.³³ Because of this, negative opiate testing on POC UDS in a patient who, by history, has not ingested an opiate in > 36 hours should be interpreted cautiously. (See Table 2.)

Unexpected positive results on UDS should prompt further investigation by sending the collected sample for confirmation testing using GC/MS, which has now become the standard of care. Even expected results on POC UDS should periodically be sent for GC/MS confirmation, especially if the prescriber’s gestalt questions abuse. Additional information is garnered by confirmatory testing, which includes the presence or absence of drug metabolites. Sometimes abusers will manipulate their UDS by putting a small amount of the prescribed medication directly into their urine sample. This quantitative testing for opiates can often provide additional clarity through metabolite detection and its respective quantity in the urine.³⁴ (See Figure 2.)

Another pitfall when interpreting UDS results stems from the chemical structures of the different opioids. Oxycodone, a commonly prescribed opioid (often used in combination with Tylenol under the trade name Percocet), may not be detected in standard urine drug screens as an opiate. Morphine and codeine are commonly prescribed natural opioids that share a similar chemical structure. Hydrocodone and oxycodone, the most commonly prescribed opioids,⁵ are classified as semi-synthetic. Methadone and fentanyl are classified as synthetic opioids and have chemical structures that are dissimilar to morphine.

Immunoassay testing dominates urine drug screening because it is simple to use, easy to automate, and provides rapid results.³⁵ For example, the enzyme multiplied immunoassay technique (EMIT) that is frequently used by laboratories for drug screening purposes targets an antibody to morphine, then binds the chemical structure, and positive or negative results are interpreted based on the amount of light emitted through the sample. Therefore, false-negative results can be caused by a variety of factors, including the cross-reactivity of the antibody used by the assay, the cutoff concentration for a positive result, and the length of time between drug ingestion and specimen acquisition.³⁶ To simplify matters, it is best to learn which opioids will not be detected by typical immunoassay testing; by doing so, the interpreting physician can use the process of elimination to more easily remember which drugs or metabolites will be detected with UDS. Oxycodone is structurally similar enough to morphine that in higher quantities (typically up to six times the cutoff limits in ng/dL of other opioids), it will bind the antibody to morphine and result in positive opiate testing. In lower quantities, however, it will result in negative opiate testing. Once again, it is vital to know the last ingestion time and amount of drug taken for proper interpretation of testing results. When prescribing oxycodone, it is typically best to order specific immunoassays targeted for the structure of oxycodone for monitoring purposes to help limit misinterpretation. Methadone and fentanyl, synthetic opioids with chemical structures significantly different from morphine, will routinely test negative for opiates on UDS. (See Table 3.)

To illustrate the importance of this, there was a recent case within the residency clinic in which a patient was prescribed methadone on a monthly basis from a methadone maintenance clinic for his prior opiate addiction. The patient was appropriately subjected to frequent random urine drug screens; however, the results consistently showed positivity for opiates, which was not consistent with his endorsed history of only methadone use. Unfortunately, the UDS had perpetually and incorrectly been interpreted as appropriately positive for opiates and the patient was maintained on his therapy. In this specific situation, confirmation testing was ordered; however, the patient refused to submit a new urine sample so the source of opiate positivity could never be confirmed. Later, the patient would end up endorsing that he “only took one Vicodin from a leftover prescription,” which would explain his opiate positivity. However, the local PDMP was queried and it showed that his last hydrocodone prescription had been filled more than 4 years earlier and no active prescription existed.

During my interview with John, I learned that this situation is not entirely uncommon. He shared with me that frequently he would sell his prescription opioids, but since confirmation testing was never sent, his urine drug testing would seemingly register as appropriate for opioids because of his ongoing and frequent heroin use.⁸ He even stated that he was “quite surprised that he was getting away with it.” Detection of heroin with confirmatory testing can be difficult because heroin quickly metabolizes into morphine and 6-monoacetylmorphine (6-AM) with 6-AM only present in the urine for 8 hours after last ingestion;³⁷ however, if found in the urine, it undisputedly confirms recent heroin use because 6-AM is a metabolite only formed from heroin use.³⁸ The latter two instances demonstrate the utility in occasionally submitting a sample of urine for confirmation through GC/MS or high-performance liquid chromatography, even among patients with seeming appropriateness on random UDS.

A White Paper published by American Society of Addiction Medicine has encouraged the wider and “smarter” use of drug testing.³⁹ This smarter testing encompasses the following points: increased use of random testing; testing not only urine but other matrices such as blood, etc.; testing for a broad and rotating panel of drugs rather than only testing for the traditional five-drug panel; improved sample collection and detection technologies to decrease sample adulteration and substitution; and consideration of the financial costs of testing in relationship to its value. Unfortunately, drug testing remains underutilized. A recently published study of a large primary care health system reported only 8% of patients receiving long-term opioid therapy — and only 24% of the highest risk patients — were evaluated via urine drug testing.⁴⁰

Data from a large national diagnostic lab’s prescription drug monitoring service found that 60% of specimens had results inconsistent with the controlled substances prescribed.⁴¹ Only 40% of patients tested positive for prescribed medications and tested negative for other drugs; 25% of patients tested negative for all drugs, including medications prescribed by their physician; 15% were negative for the prescribed drug and positive for another unprescribed drug; and 20% were positive for both the prescribed medications and other drugs. Marijuana, which was present in more than one-fourth of specimens, was the most frequently detected non-prescribed drug among patients.⁴²

Other sources of tests, such as blood, saliva, sweat, nails, and hair, are commercially available and may have advantages for selected patients. Although blood typically will have a shorter duration of drug and metabolite presence than urine, it does provide unequivocal positive patient identification and offers the clinician invaluable information regarding steady-state drug concentrations that can help in identifying patients with low concentrations who may be underdosed or diverting prescriptions or those with high concentrations who may be having toxic effects from improper dosing, pharmacogenetic variations, or obtaining drugs from other sources.

SUMMARY AND CONCLUSIONS

Physicians are now daunted with an unfortunate reality that the prescription opiates they have prescribed for well-intended use are sometimes misused or abused. And unfortunately, the health care profession has contributed to the growing heroin epidemic, at least to some degree. In a desire to alleviate suffering, physicians occasionally are only serving to propagate and fuel addiction. The challenge for physicians becomes how to prescribe opiates in a manner that will minimize abuse/misuse while maximizing benefit, alleviating pain, and improving functional outcomes for those who require opioids as a last resort. Prescribing opioids responsibly is an attainable goal, but it requires that the physician have a well-rounded perspective into the challenge faced.

Physicians must accept that people will continue to lie, and addicts have crafted their ability to lie better than most. Some patients will be successful at manipulating even the most astute physician. Well-intended opioids will be diverted, stolen, abused, and misused. Regrettably, some degree of pain will just have to exist and some under-treatment of legitimate pain will be the cost of being a diligent prescriber.

A recent perspective article published in the New England Journal of Medicine suggested that “suffering may be related as much to the meaning of pain as to its intensity. Persistent helplessness and hopelessness may be the root causes of suffering for patients with chronic pain yet be reflected in a report of high pain intensity.”¹⁰ Perhaps a paradigm shift is needed in the treatment of chronic pain where the clinician and the patient ensure a complete understanding at the outset of therapy that chronic pain is just that — chronic. The expectation that chronic pain will be cured only sets the stage for therapy failure. It perpetuates the feelings of persistent helplessness and hopelessness that Ballantyne and Sullivan have suggested.

However, unique circumstances do exist in which chronic opioid therapy can be beneficial, and in these circumstances, it should not be withheld. The prescriber then must treat each case as an investigation: digging deep into the chart and rooting out any and all risks. Due diligence must be given to the necessity and appropriateness of each prescription dispensed. Primary care physicians must proceed cautiously and judiciously rather than mindlessly refilling the prescription. Establishing medication agreements, utilizing PDMPs, checking and knowing how to properly interpret urine drug screens, and setting specific goals for therapy prior to initiation of opioids will augment the physician’s armamentarium of tools, which will serve to prescribe opioids safely and effectively while minimizing adverse risks such as diversion, abuse, and misuse.

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