There has been increasing concern about widespread opioid drug prescriptions in United States health care settings. In 2012, 259 million prescriptions were written for opioids, which is more than enough to give every American adult a bottle of pills.1 Although the primary medical use of opioids is as an analgesic, this also carries a risk for misuse. According to a 2015 National Survey on Drug Use and Health survey, the most commonly reported reason for misuse of prescription opioids was to relieve physical pain (63.4%).2
Opioid misuse has led to a staggering amount of lost lives and economic costs. In 2015, a total of 20,101 overdose deaths were related to prescription pain relievers.3 From 1999 to 2010, prescription pain reliever overdose deaths among women increased more than 400%, compared to 237% among men.4 The Council of Economic Advisers in November 2017 reported that the opioid drug problem has reached crisis levels in the US, and the economic cost of the opioid crisis in 2015 was $504 billion or 2.8% of the gross domestic product.5
There is concern that addiction to prescription opioids may lead to use of additional dangerous substances. From the year 2008 to 2010, about 82.6% of Americans using heroin (including those in treatment) reported misusing prescription opioids first; this was an increase from 64.1% between 2002 and 2004.6 In a survey conducted in 2014, it was found that 94% of people in treatment for opioid addiction stated that they chose to use heroin because prescription opioids were even more expensive and harder to obtain.7
Challenges in Diagnosis
In cases where a patient may minimize use, diagnosing opioid use disorder (OUD) may be more complex and require analysis of a patient's behavioral patterns and using multiple sources of information to confirm clinical suspicion.
Laboratory testing may be helpful. Although opioid use itself is not associated with liver injury, chronic use of acetaminophen-containing formulations may present with elevated liver enzymes.8 Urine toxicology screens that are positive for opioids help confirm suspicion of use in those who deny taking narcotics. However, the caveat is that urine toxicology screens have limitations, as they only detect compounds metabolized to morphine (heroin, codeine, morphine, poppy seeds). Standard urine drug screens may not detect synthetic opioids (fentanyl, oxymorphone, meperidine, propoxyphene, buprenorphine, methadone), and have variable cross-reactivity with hydrocodone, hydromorphone, and oxycodone.9 On mental status examination, it is also important to recognize signs of opioid withdrawal. A common cold may mimic withdrawal, but mydriasis, frequent yawning, elevated vital signs, tremor, and piloerection are more withdrawal-specific signs.
It is important to recognize that physiological dependence alone is neither sufficient nor required to cause addiction and, in fact, is mediated by different physiologic pathways.10 Those who are physiologically dependent on opioids for years may exhibit a natural and expected risk of tolerance and withdrawal, but this may not qualify as criteria for OUD in persons undergoing properly medically supervised opioid therapy. However, if the patient develops tolerance and withdrawal stemming from compulsive use, then criteria of OUD are met.
The presence of an OUD may be conceptualized with the three “C's of addiction”: loss of Control, Compulsion to use (or Cravings), and continued use despite adverse Consequences.11 Loss of control may be demonstrated by the inability to ration supply of medication, and the patient may frequently run out early. This may be evidenced by requesting early refills or replacement of lost refills or prescriptions. Compared to nonmisusers, misusers of opiates fill 7 times as many prescription opioids in 1 year, have been prescribed 4 times as many different type of opioids, use 3 times as many pharmacies, and are over 9 times more likely to receive at least one early refill.12 The primary purpose of the Prescription Drug Monitoring Program (PDMP) is to reduce the overprescribing of controlled substances by health practitioners and to curtail the diversion and misuse of opioid analgesics.13 Its use by health care providers has been inconsistent over the past years,14 although several states are now requiring mandatory consultation of the PDMP databases before prescribing controlled substances.15
It can also be challenging to distinguish an actual use disorder from pseudoaddiction. Pseudoaddiction describes a phenomenon in which patients who are treated with opioids for pain may exhibit seemingly aberrant behaviors when analgesia is inadequate. They may display preoccupation with seeking opioid medication, switch providers, run out of medications early, or use medications from other sources. When adequate pain control is achieved (either through adequate dose or alternative treatment), the aberrant behavior ceases. On the other hand, a patient with OUD may discontinue aberrant behavior once the request for escalated doses is met, but cessation of this behavior is usually only temporary.16
Finally, the National Institute on Drug Abuse (NIDA) suggests using their quick screen and NIDA-modified ASSIST (The Alcohol, Smoking and Substance Involvement Screening Test) questionnaires for identifying OUD in a general medical setting.17 Multiple other screening tools have been developed to help monitor and identify an at-risk population undergoing or considering chronic opioid pain management. This includes the modified Cut-Annoyed-Guilty-Eye questionnaire, Prescription Drug Use Questionnaire (42 item), and Drug Abuse Screening Test (28 item).18
Treatment of Opioid Use Disorder
Understanding the pharmacology of opioids is important for eventual treatment planning of OUD. There are three classic opioid receptors: mu, delta, and kappa. A new receptor, nociceptin, also belongs to a nonopioid branch of the opioid receptor family. Most of the opioids used in clinical practice today have their primary action on the mu receptor.19,20 These receptors typically belong to a G-protein coupled family of receptors and are found widely in the body. Inhibition of neurotransmitter release via hyperpolarization is considered the primary mechanism responsible for the clinical effects.19,20 This may include analgesia, but may also be lead to overdose death via respiratory depression. On the other hand, receptor antagonists naloxone and naltrexone can be used to reverse the effects of agonists at all three of the classical opioid receptors.19
After a patient is diagnosed with OUD, several important decisions must be made. If the patient is actively in withdrawal from opioids, detoxification using a buprenorphine or methadone taper may be extremely helpful as they are mu-receptor partial agonists and full agonists, respectively.
If those options are not available, supportive care with antiemetics, antidiarrheals, and sedatives may be helpful to ameliorate symptoms. To reduce noradrenergic excess during withdrawal, the alpha-2-adrenergic receptor agonists clonidine and lofexidine are additional viable options. Lofexidine may have less risk of hypotension and sedation compared to clonidine.21 Although the use of clonidine remains off-label in the US, lofexidine was recently approved by the US Food and Drug Administration in March 2018 as the first nonopioid treatment for withdrawal symptoms that can be continued for up to 14 days.22
Once detoxification is initiated, the next step in treatment planning involves deciding between longer-term treatment that is abstinence-based or medication-assisted (Figure 1). Use of abstinence-based treatment does not involve medications specifically targeting OUD. However, for some, it may be more helpful to transition to medication-assisted treatment (MAT) with a full mu-receptor antagonist (naltrexone), full agonist (methadone), or partial agonist (buprenorphine).
Representation of various treatment options for opioid use disorder.
Although some patients may do well in abstinence-based treatment, providers must also acknowledge the high rates of relapse after detoxification in a residential treatment setting, with estimates of up to 91%.23 Predictors of relapse after inpatient detoxification may include history of greater amount of use, longer duration of use, positive family history, and past attempt of opioid detoxification.24 Having multiple predictors may suggest a role for MAT over abstinence-based treatment. If MAT is chosen, a decision to prescribe a specific medication may involve many factors, including patient preference, past treatment response, presence of chronic pain, illness severity, lifestyle, and personal beliefs about recovery.
If the patient is enrolled in MAT, a provider should keep in mind that medication alone may not be sufficient enough for recovery. A large role of the medication is to help to relieve withdrawal, reduce cravings substantially, reduce overdose risk, improve treatment retention, and allow for improved engagement in psychosocial interventions and lifestyle changes. There is no “one size fits all” treatment, and a decision should be made together with the patient. The benefit of agonist medications, such as buprenorphine and methadone, is that they use the harm-reduction approach. This embraces the idea that patients who are maintained on these medications are still physiologically dependent on an opioid; however, there is an associated reduction in legal issues, an improved quality of life, reduced mortality, and reduced rates of blood-borne illnesses.25
Buprenorphine is becoming available in a variety of forms to help improve treatment compliance. Although sublingual films and tablets have been available, newer formulations now exist in the US including 6-month subdermal implants and monthly intramuscular injections.26 An assumed benefit of the intramuscular injections and implant formulations is that they may help improve compliance and reduce the risk of diversion that can occur with films or tablets.27
On the other hand, some other patients may prefer to use the nonnarcotic, mu-receptor antagonist option of naltrexone to avoid being physiologically dependent on a medication. Naltrexone comes in two formulations: oral and intramuscular monthly extended-release (NTX-XR). Although there is concern that the oral form may not be very effective in relapse prevention or retention due to low adherence, NTX-XR may confer some benefits in craving reductions, retention, and abstinence rates.28 It may be more challenging to initiate onto NTX-XR, but the relapse-free survival was similar between those who successfully initiated NTX-XR and buprenorphine.29 Another study found that treatment retention and the proportion of opioid-negative drug screens with NTX–XR was noninferior to that with buprenorphine.30 However, in both of these studies, patients were randomized to the medication treatment group. In a clinical setting, specific patient characteristics may help guide medication preference (Table 1).
Medication-Assisted Treatment Options
Once a patient is enrolled in MAT, it is also possible to transition from an opioid agonist to naltrexone and vice versa. However, when switching from an opioid agonist to naltrexone, there typically needs to be a sufficient washout period of the agonist (at least 7–10 days); otherwise the premature administration of NTX-XR could lead to precipitated withdrawal symptoms.31 Yet, there is a building body of evidence that naltrexone can be initiated soon after detoxification from an opioid agonist such as buprenorphine, by using small but increasing oral naltrexone doses, followed by administration of NTX-XR.32
As mentioned earlier, patients on MAT are recommended to be involved in psychosocial interventions, which may include, but are not limited to 12-step groups, Self-Management and Recovery Training recovery, and individual or group therapy. The 12-step groups have a wide variety of benefits and provide support and a “sponsor” to mentor the patient during high-risk situations. At the same time, many patients may struggle with the idea of taking medication while attending 12-step groups because some attendees may have a different view about medications. This should not necessarily discourage patients from going to 12-step groups, but it may be of benefit to find a “home group” where one feels well accepted for their own individual treatment. Offering P-11 (pamphlet 11) groups is an additional option, as they follow the same 12-step principles but have increased acceptance to those who have mental illness and are on prescribed medications.
Additional psychiatric interventions and collaboration with primary care providers and specialists can help to address chronic pain that may increase a patient's relapse risk. It is a well-established fact that patients with both depression and pain are those who present to the primary care physician offices most frequently.33,34 The relationship between pain and depression can be complex to manage as depression can influence pain syndromes and vice versa. This makes it important for the providers to recognize and treat depression and pain simultaneously so that the patient gets relief for both disorders.
It is well-known that dysregulation of the neurotransmitters serotonin and norepinephrine is linked to both depression and pain.33 Thus, antidepressants that inhibit the reuptake of both serotonin and norepinephrine, such as venlafaxine and duloxetine, are the first-line treatments in patients who are depressed with physical symptoms.33–35 Selective serotonin reuptake inhibitors are not as effective in treating pain as compared to serotonin–norepinephrine reuptake inhibitors, but they are used because they are treating the depressive symptoms in patients with pain.34 The other antidepressants that are efficacious include the tricyclic antidepressants amitriptyline and nortriptyline in management of neuropathic pain.34,35 Other psychotropic medication used to treat pain include pregabalin and gabapentin. Topamax and valproic acid are also used as adjuncts to treat migraines.34
The most widely used psychological treatment for persistent pain is cognitive-behavioral therapy (CBT), which targets beliefs about pain. This includes education about pain, learning coping skills such as relaxation or problem-solving, and finally practicing the skills at home.36
CBT helps patients to understand how their own cognitive responses to pain influence their pain experience and to recognize the role that their own coping efforts can play in pain control. Complementary and alternative medicine used in the treatment of pain includes a variety of treatment options that include acupuncture, yoga, hypnosis, guided imagery, biofeedback, aromatherapy, herbal remedies, massages, and many others.36
- Centers for Disease Control and Prevention. Opioid painkiller prescribing. Where you live makes a difference. http://www.cdc.gov/vitalsigns/opioid-prescribing/. Accessed July 12, 2018.
- Han B, Compton WM, Blanco C, Crane E, Lee J, Jones CM. Prescription opioid use, misuse, and use disorders in U.S. adults: 2015 National Survey on Drug Use and Health. Ann Intern Med. 2017;167(5):293–301. doi:. doi:10.7326/M17-0865 [CrossRef]
- Rudd RA, Seth P, David F, Scholl L. Increases in drug and opioid-involved overdose deaths - United States, 2010–2015. MMWR Morb Mortal Wkly Rep. 2016;65(5051):1445–1452. doi:. doi:10.15585/mmwr.mm655051e1 [CrossRef]
- Centers for Disease Control and Prevention. Prescription painkiller overdoses. A growing epidemic, especially among women. http://www.cdc.gov/vitalsigns/prescriptionpainkilleroverdoses/index.html. Accessed July 12, 2018.
- Whitehouse.gov. Council of economic advisers report: the underestimated cost of the opioid crisis. https://www.whitehouse.gov/briefings-statements/cea-report-underestimated-cost-opioid-crisis/. Accessed July 24, 2018.
- Jones CM. Heroin use and heroin use risk behaviors among nonmedical users of prescription opioid pain relievers - United States, 2002–2004 and 2008–2010. Drug Alcohol Depend. 2013;132(1–2):95–100. doi:. doi:10.1016/j.drugalcdep.2013.01.007 [CrossRef]
- Cicero TJ, Ellis MS, Surratt HL, Kurtz SP. The changing face of heroin use in the United States: a retrospective analysis of the past 50 years. JAMA Psychiatry. 2014;71(7):821–826. doi:. doi:10.1001/jamapsychiatry.2014.366 [CrossRef]
- Michna E, Duh MS, Korves C, Dahl JL. Removal of opioid/acetaminophen combination prescription pain medications: assessing the evidence for hepatotoxicity and consequences of removal of these medications. Pain Med. 2010;11(3):369–378. doi:. doi:10.1111/j.1526-4637.2010.00811.x [CrossRef]
- Warner E, Lorch E. Laboratory diagnosis. In: Ries RK, ed. The ASAM Principles of Addiction Medicine. 3rd ed. Philadelphia, PA: Wolters Kluwer Health Adis; 2014:332–343.
- Nestler E. From neurobiology to treatment: progress against addiction. Nat Neurosci. 2002;5:1076–1079. doi:. doi:10.1038/nn945 [CrossRef]
- Savage SR, Joranson DE, Covington EC, Schnoll SH, Heit HA, Gilson AM. Definitions related to the medical use of opioids: evolution towards universal agreement. J Pain Symptom Manage. 2003;26(1):655–667. doi:10.1016/S0885-3924(03)00219-7 [CrossRef]
- Rice JB, White AG, Birnbaum HG, Schiller M, Brown DA, Roland CL. A model to identify patients at risk for prescription opioid abuse, dependence, and misuse. Pain Med. 2012;13(9):1162–1173. doi:. doi:10.1111/j.1526-4637.2012.01450.x [CrossRef]
- Finley EP, Garcia A, Rosen K, McGeary D, Pugh MJ, Potter JS. Evaluating the impact of Prescription Drug Monitoring Program: a scoping review. BMC Health Serv Res. 2017;17:420. doi: . doi:10.1186/s12913-017-2354-5 [CrossRef]
- Hildebran C, Cohen DJ, Irvine JM, et al. How clinicians use prescription drug monitoring programs: a qualitative inquiry. Pain Med. 2014;15(7):1179–1186. doi:. doi:10.1111/pme.12469 [CrossRef]
- Haffajee RL, Jena AB, Weiner SG. Mandatory use of prescription drug monitoring programs. JAMA. 2015;313(9):891–892. doi:. doi:10.1001/jama.2014.18514 [CrossRef]
- Savage SR. Opioid therapy of pain. In: Ries RK, ed. The ASAM Principles of Addiction Medicine. 3rd ed. Philadelphia, PA: Wolters Kluwer Health Adis; 2014:1500–1529.
- National Institute on Drug Abuse. Screening for drug use in general medical settings. https://www.integration.samhsa.gov/clinical-practice/sbirt/NIDA_screening_for_drug_use.pdf. Accessed July 24, 2018.
- Zgierska A, Fleming MF. Screening and brief intervention. In Ries RK, ed. The ASAM Principles of Addiction Medicine. 3rd ed. Philadelphia, PA: Wolters Kluwer Health Adis; 2014:297–331.
- Pathan H, Williams J. Basic opioid pharmacology: an update. Br J Pain. 2012;6(1):11–16. doi:. doi:10.1177/2049463712438493 [CrossRef]
- Feng Y, He X, Yang Y, Chao D, Lazarus LH, Xia Y. Current research on opioid receptor function. Curr Drug Targets. 2012;13(2):230–246. doi:10.2174/138945012799201612 [CrossRef]
- Grodetzky CW, Walsh SL, Martin PR, Saxon AJ, Gullo KL, Biswas K. A phase III, randomized, multi-center, double blind, placebo controlled study of safety and efficacy of lofexidine for relief of symptoms in individuals undergoing inpatient opioid withdrawal. Drug Alcohol Depend. 2017;176:79–88. doi:. doi:10.1016/j.drugalcdep.2017.02.020 [CrossRef]
- US Food and Drug administration. FDA approves the first non-opioid treatment for management of opioid withdrawal symptoms in adults. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm607884.htm. Accessed July 12, 2018.
- Smyth BP, Barry J, Keenan E, Ducray K. Lapse and relapse following inpatient treatment of opiate dependence. Ir Med J. 2010;103(6):176–179.
- Chalana H, Kundal T, Gupta V, Malhari AS. Predictors of relapse after inpatient opioid detoxification during 1-year follow-up [published online ahead of print September 18, 2016]. J Addict. doi:10.1155/2016/7620860 [CrossRef].
- Stancliff S, Phillips BW, Maghsoudi N, Joseph H. Harm reduction: front line public health. J Addict Dis. 2015;34(2–3):206–219. doi:. doi:10.1080/10550887.2015.1059651 [CrossRef]
- US Food and Drug Administration. FDA approves first once-monthly buprenorphine injection, a medication-assisted treatment option for opioid use disorder. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm587312.htm. Accessed July 24, 2018.
- Rosenthal RN, Goradia VV. Advances in the delivery of buprenorphine for opioid dependence. Drug Des Devel Ther. 2017;11:2493–2505. doi:. doi:10.2147/DDDT.S72543 [CrossRef]
- Krupitsky E, Nunes EV, Ling W, Illeperuma A, Gastfriend DR, Silverman BI. Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicenter randomized trial. Lancet. 2011;377:1506–1513. doi:. doi:10.1016/S0140-6736(11)60358-9 [CrossRef]
- Lee JD, Nunes EV, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicenter, open-label, randomized controlled trial. Lancet. 2018;391:309–318. doi:. doi:10.1016/S0140-6736(17)32812-X [CrossRef]
- Tanum L, Solli KK, Latif Z, et al. Effectiveness of injectable extended-release naltrexone vs daily buprenorphine-naloxone for opioid dependence--a randomized clinical noninferiority trial. JAMA Psychiatry. 2017;74 (12):1197–1205. doi:. doi:10.1001/jamapsychiatry.2017.3206 [CrossRef]
- Physicians Desk Reference. Naltrexone - drug summary. http://www.pdr.net/drug-summary/vivitrol?druglabelid=1199&id=2886. Accessed July 24, 2018.
- Sullivan M, Bisaga A, Pavicova M, et al. Long-acting injectable naltrexone induction: a randomized trial of outpatient opioid detoxification with naltrexone versus buprenorphine. Am J Psychiatry. 2017;174(5):459–467. doi:. doi:10.1176/appi.ajp.2016.16050548 [CrossRef]
- Trivedi MH. The link between depression and physical symptoms. Prim Care Companion J Clin Psychiatry. 2004;6(suppl 1):12–16.
- Andersson HI, Ejlertsson G, Leden I, Schersten B. Impact of chronic pain on health care seeking, self care, and medication. Results from a population-based Swedish study. J Epidemiol Community Health. 1999;53:503–509. doi:10.1136/jech.53.8.503 [CrossRef]
- Liu WQ, Kanungo A, Toth C. Equivalency of tricyclic antidepressants in open-label neuropathic pain study. Acta Neurol Scand. 2014;129(2):132–141. doi:. doi:10.1111/ane.12169 [CrossRef]
- Singh P, Chaturvedi A. Complementary and alternative medicine in cancer pain management: a systematic review. Indian J Palliat Care. 2015;21(1):105–115. doi:. doi:10.4103/0973-1075.150202 [CrossRef]
Medication-Assisted Treatment Options
|Mechanism at mu receptor
|Formulations (FDA approved for opioid use disorder)
||IM monthly injection
SL or buccal film
6-month subdermal implant
||Monthly IM injection
|Potential for physiological dependence
||Daily initially with eventual 30-day take-outs
||Generally greater flexibility than methadone
||Oral (usually daily dosing)
Monthly IM injection
||Part of a federally regulated opiate treatment program
||Provider needs x-waiver
||No specific regulation
||Standard of care in pregnancy
||Less studies than methadone but good safety evidence; may require shorter treatment duration and less medication to treat neonatal abstinence syndrome compared to methadone; standard of care in pregnancy
||Very limited data
|Use in detoxification
||Possible to use orally in small, gradually escalating doses