Opioid Dependence Hits Maternity Wards and NICUs

The rising problem of opioid abuse affects pregnant women and their infants, who often need care in the neonatal intensive care unit.

As the prevalence of opiate misuse and abuse soars, it has become evident that even pregnant women are affected by the deeply rooted neurobiologic cravings of addiction. Increasingly considered a chronic, multidimensional disease, addiction extends well beyond a simple behavioral urge. The far-reaching condition is a product of genetic, psychosocial, and environmental factors that ultimately lead to the compulsive and continued use of a substance despite harm.

The number of pregnant women addicted to opioids and the number of infants born experiencing withdrawal symptoms (clinically known as neonatal abstinence syndrome [NAS]) have risen sharply over the past decade.¹ Although the prevalence of illicit drug use among pregnant women has been documented (estimated at 7.4% in adults and 16.2% in teens),² national estimates of the incidence of NAS over time in the context of maternal opiate use at time of delivery have been largely lacking.

The Burden of NAS

Prompted by analyses indicating a rise in the occurrence of NAS, researchers recently conducted a study using national data to examine patterns in the incidence of NAS and maternal opiate use at the time of delivery. Investigators looked at 2 large databases, which included a representative sample of patients from across the country, and found that the number of pregnant mothers using opiates jumped 5-fold from 2000 to 2009 (increasing from 1.19 to 5.53 per 1000 hospital births per year).¹ Likewise, the incidence of NAS among newborns rose 3-fold (from 1.20 to 3.39 per 1000 hospital births per year). In the United States, the investigators estimated, a baby is born every hour with symptoms of opioid withdrawal.¹

NAS is characterized by a constellation of symptoms including increased irritability, hypertonia, tremors, feeding intolerance, emesis, watery stools, seizures, and respiratory distress.³ These babies cry inconsolably, are not able to tolerate any light or sound, and even exhibit signs of trauma on limbs and fingers from repeatedly striking them due to constant myoclonic jerks.

Although not all opiate-exposed newborns exhibit signs of withdrawal (as evidenced by the outpacing growth of maternal opiate use versus the incidence of NAS),⁴ symptoms of NAS-related withdrawal have been described in 60% to 80% of newborns exposed to heroin or methadone in utero.⁴ These infants, like the cocaine-exposed babies of the 1980s, are entering a world in which relatively little is known about the long-term effects on their development. Few doctors are willing to treat pregnant opiate addicts, and there is no universally accepted standard ofcare for their babies, partly due to the unfeasibility of conducting research on pregnant women and newborns.

The only certainty is that infants with NAS require tremendous medical resources because they are more likely to have low birth weights, respiratory complications, and various birth defects, along with an average 16-day length of stay (LOS) in the hospital.¹ Newborns with NAS are frequently cared for in neonatal intensive care units (NICUs). Because they are typically treated for withdrawal symptoms with opiates (eg, oral morphine, methadone), potentially in combination with phenobarbital or clonidine, they require stringent monitoring and a painstaking weaning process.

In many of these infants, opiate withdrawal is compounded by maternal comorbid polydrug exposure and psychiatric medications (eg, antidepressants, benzodiazepines). These agents have their own withdrawal syndromes that may further extend the LOS.⁵ As expected, the intensive medical care required for NAS comes with a substantial economic burden. Hospital charges for infants with NAS have climbed from $39,400 in 2000 to $53,400 in 2009, with Medicaid cited as the predominant payer for mothers using opiates (60.0%) and newborns with NAS (78.1%).¹

Trends in Opioid Abuse

These findings come on the heels of several reports indicating a marked increase in the use of opioids within the United States. Between 1999 and 2008, sales and deaths related to opiate analgesics quadrupled, and licit drugs (ie, opioids) have recently replaced illicit drugs (eg, cocaine, heroin) as the most common cause of fatal drug poisoning in the United States.⁶ As of 2005, nonmedical use of oxycodone had surpassed that of many historically popular illicit drugs such as marijuana, cocaine, and heroin.⁷

Instead of more difficult to obtain illicit drugs, many addicts initially turn to—and prefer—opioids, which are comparatively easier to acquire due to their availability for legitimate use. Young women are nearly as likely as men to abuse opioids, which is seen as a major contributor to the increased incidence of opiate-dependent newborns.⁵

Methadone is more likely involved in overdose deaths than any other prescription drug; ironically, methadone maintenance therapy is also the standard treatment for opioid dependence during pregnancy.

Pregnant women who enroll in methadone programs are treated with a stable regimen, which is intended to prevent withdrawal and reduce risk of accidental overdose. They are also given improved access to the health care system, including drug treatment and obstetric care. However, even within these seemingly structured programs, methadone therapy is idiosyncratic, nonstandardized, and subjectively based on maternal withdrawal symptoms as gestation progresses. Women continue to have higher rates of adverse maternal and neonatal outcomes (as well as relapse and continued illicit drug use) than the general population, most likely as a result of underlying medical and social circumstances.^8-10

Buprenorphine: A New Option

During the past several years, buprenorphine has emerged as an alternative to methadone for narcotic replacement therapy. As a partial agonist at the mu receptor and an antagonist at the kappa receptor, buprenorphine decreases opioid craving and withdrawal, but differs from full mu-opioid agonists (eg, methadone, morphine) in that it generally causes less sedation, has a “ceiling effect” on analgesia and respiratory depression, and has a lower potential for abuse and diversion (especially when combined with the opioid antagonist naloxone).^11,12 The implications of buprenorphine’s kappa receptor antagonism are not well understood, but may be attributed to the agent’s mild antidepressant effects.

Although buprenorphine is safer than methadone in overdose situations, it may still cause significant respiratory depression, particularly when administered intravenously. In fact, a number of deaths have been associated with intentional misuse of buprenorphine intravenously, usually in combination with other depressants such as benzodiazepines, alcohol, and other opioids.^11,13 Although chronic administration of buprenorphine may still result in dependence, the withdrawal syndrome is milder and may have a delayed onset compared with full opioid agonists.¹³

In examining efficacy of buprenorphine in pregnant women, 1 randomized, double-blind trial found that newborns whose mothers were treated with buprenorphine required 89% less morphine and spent 43% less time in the hospital.¹⁴ However, researchers have found no differences in the rate of NAS diagnosis, and women treated with buprenorphine have demonstrated a higher dropout rate, suggesting that this agent may not treat maternal addiction as effectively as methadone.⁵

The most notable advantage of using buprenorphine is its accessibility. Buprenorphine, a Schedule III agent, may be prescribed by private physicians and dispensed at pharmacies, whereas methadone can only be distributed though specialized clinics, limiting its use to less than 15% of individuals with opioid dependence.¹² Methadone treatment programs have expanded rapidly, but the burden of addiction on state Medicaid budgets threatens the livelihood of recently established programs, despite increased need.

Pharmacy’s Role

The most straightforward solution to the epidemic of opioid abuse is treatment of drug addiction prior to pregnancy and, better yet, prevention of opioid abuse in the first place. Pharmacists can play a vital role by remaining vigilant when faced with patients who claim multiple prescription losses, repeatedly present opioid prescriptions from emergency departments, show evidence of deterioration, and are repeatedly resistant to changes in therapy despite evidence of physical or psychological opioid effects.¹⁵ Although addiction and abuse are serious issues, they should not prevent legitimate use of opioids, because research indicates that most appropriately treated patients will not become addicted.

Dr. Beyzarov is scientific director for the Pharmacy Times Office of Continuing Professional Education.

References

1. Patrick SW, Schumacher RE, Benneyworth BD, et al. Neonatal Abstinence Syndrome and Associated Health Care Expenditures: United States, 2000-2009. JAMA. 2012 Apr 30.

2. Substance Abuse and Mental Health Administration. Office of Applied Studies, Results From the 2010 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-41, HHS Publication No. (SMA) 11-4658. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2011.

3. American Academy of Pediatrics Committee on Drugs. Neonatal drug withdrawal. Pediatrics. 1998;101(6):1079—1088.

4. Doberczak TM, Kandall SR, Wilets I. Neonatal opiate abstinence syndrome in term and preterm infants. J Pediatr. 1991;118(6):933—937.

5. Patrick SW, Schumacher RE, Benneyworth BD, et al. Neonatal Abstinence Syndrome and Associated Health Care Expenditures: United States, 2000-2009. JAMA. 2012 Apr 30.

6. Paulozzi LJ et al. Increasing deaths from opioid analgesics in the United States. Pharmacoepidemiol Drug Safety. 2006;15(9):618-27.

7. Results from the 2005 survey on drug use and health. DHHS Publication No. SMA D6-4194,2006.

8. Almario CV, Seligman NS, Dysart KC, et al. Risk factors for preterm birth among opiate-addicted gravid women in a methadone treatment program. Am J Obstet Gynecol. 2009;201(3):326.e1—326.e6.

9. Britton KA, Mahaffey D, Brizendine E, et al. Methadone maintenance in pregnancy: a reappraisal. Am J Obstet Gynecol. 1998;179(2):459—463.

10. Jones HE, Kaltenbach K, Heil SH, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010;363(24):2320—2331

11. Srivastava A, Kahan M. Buprenorphine: a potential new treatment for opioid dependence. CMAJ. June 2006; 174(13):1835-1836

12. Raisch DW, Fye CL, Boardman KD, Sather MR. Opioid dependence treatment, including buprenorphine/naloxone. Ann Pharmacother. 2002 Feb;36(2):312-21

13. Information for pharmacists: SUBOXONE® (buprenorphine HCl/naloxone HCl dihydrate, sublingual tablet) and SUBUTEX® (buprenorphine HCl, sublingual tablet). Accessed on 8/23/2008 at http://www.fda.gov/cder/foi/label/2002/20732pharmacist.pdf

14. Jones HE, Kaltenbach K, Heil SH, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010;363(24):2320—2331

15. Passik SD, Kirsh KL, Whitcomb L, Dickerson PK, Theobald DE. Pain clinicians' rankings of aberrant drug-taking behaviors. J Pain Palliat Care Pharmacother. 2002;16:39-49