June 2nd 2012

Do we need fetal echocardiograms for women drinking during pregnancy?

A recent article finds an odds ratio of 3 for cardiac defects for binge alcohol users and an odds ratio of 12 when binge drinkers / smokers are compared to non smoker / non drinkers. I don't have access to the full text (yet) so I don't know the absolute risk.  This is a case control study retrospectively looking at drinking & smoking in women who had babies with defects compared to normal babies.  It may be effected by recall bias.  Binges for the 3 months prior to pregnancy were looked at.  They don't say in the abstract how many drinks make a binge.

J Womens Health (Larchmt). 2012 Jan;21(1):26-34. Epub 2011 Sep 6.
The association between maternal alcohol use and smoking in early pregnancy and congenital cardiac defects.
Mateja WA, Nelson DB, Kroelinger CD, Ruzek S, Segal J.

BACKGROUND:
Alcohol use is an extremely prevalent but preventable risk factor among women seeking to become pregnant. Many women continue to use alcohol in the early stages of pregnancy before they are aware they are pregnant. Research is unclear about the role of maternal alcohol use during pregnancy and congenital cardiac defects, one of the leading types of birth defects in the United States.
METHODS:
Data from the Pregnancy Risk Assessment Monitoring Survey (PRAMS) were used to examine maternal alcohol use and its association with congenital cardiac defects. Various measures of alcohol use in the 3 months prior to pregnancy, as well as smoking and other risk factors for congenital cardiac defects, were linked to birth certificate data for nine states over a 10-year period (1996-2005). In this case-control study, cases included infants with a congenital cardiac defect indicated on the birth certificate, and the control group consisted of healthy, normal weight infants with no indication of a congenital abnormality on their birth certificate. Complex samples logistic regression models were used to study the relationships between several measures of alcohol use, including binge drinking and binge drinking on more than once occasion, and the interaction between alcohol use and smoking with the odds of congenital cardiac defects.

RESULTS:
A significant increase in congenital cardiac defects was found among mothers who reported binge drinking more than once in the 3 months prior to pregnancy compared to mothers who did not report binge drinking (adjusted odds ratio [aOR] 2.99, 95% confidence interval [CI] 1.19-7.51). There was a significant interaction between any binge drinking or binge drinking more than once and cigarette use, which corresponded to a substancial increase in congenital cardiac defects (aOR 12.65, 95% CI 3.54-45.25 and aOR 9.45, 95% CI 2.53-35.31, respectively).
CONCLUSIONS:
Multiple episodes of maternal binge drinking in early pregnancy may increase the odds of congenital cardiac defects, and we found this relationship was more dramatic when combined with maternal smoking.
PMID: 21895513 [PubMed - indexed for MEDLINE]

 NMDA antagonists

There has been a fair bit of research showing that NMDA antagonists can prevent the development of opiate tolerance / dependence.  That makes sense as NMDA appears to mediate neuroplasticity (aka learning).  But preventing dependence may not do much to help our patients who are already dependent.  I am always looking for evidence as to whether drugs that work on this pathway would help people experiencing opiate withdrawal

This brief letter

J Blood Med. 2012;3:15-6. Epub 2012 May 9.
7-Nitroindazole and its rapidly emerging role in opioid pain management and withdrawal.  Kapoor S.  PMID: 22629117 [PubMed - in process]

Pointed me to this 1999 article 

Eur J Pharmacol. 1999 Jul 21;377(2-3):183-6.
Differential effects of nitric oxide synthase inhibitor, 7-nitroindazole, on discriminative stimulus and somatic effects of naloxone in morphine-dependent rats.
Medvedev IO, Dravolina OA, Bespalov AY.

Our previous report suggested that antagonists acting at NMDA receptors attenuate discriminative stimulus effects of naloxone in morphine dependent rats. Nitric oxide (NO) is a putative second messenger which mediates NMDA receptor activation. The present study evaluated behavioral effects of NO synthase inhibitor, 7-nitroindazole in morphine-dependent rats trained to discriminate 0.1 mg/kg naloxone from saline. 7-Nitroindazole did not significantly affect naloxone's discriminative stimulus effects but decreased naloxone-induced weight loss and abolished expression of several withdrawal signs--diarrhea, scream on touch, tremor and 'wet dog'-like shaking suggesting different mechanisms for subjective and somatic components of opioid withdrawal.
PMID: 10456428 [PubMed - indexed for MEDLINE] 

Which shows at least one molecule interfering with the NMDA pathway decreased naloxone induced withdrawal symptoms in opiate dependent rats. This is not an available medication.  I am not (yet) aware of any studies showing decreased symptoms in humans by NMDA drugs.  

Salvia

There is a report of GI symptoms with withdrawal from smoking Salvia.

Salvia is an herbal product smoke for hallucinatory purposes.  Wikipedia describes it as "a potent and selective κ-Opioid.  However, it is an even more potent D2 receptor partial agonist" the latter presumably accounting for its hallucinogenic effects.  This product is not illegal in most states at this time. 

A Report of Nausea and Vomiting with Discontinuation of Chronic Use of Salvia divinorum.
Travis CR, Ray GA, Marlowe KF.

Introduction. This is the first reported case of gastrointestinal symptoms associated with withdrawal after chronic use of this substance. Case Presentation. A 51-year-old Caucasian woman was referred to a hospital with a 3-day history of nausea, vomiting, diarrhea, and abdominal discomfort. She reported no sick family members or contact with anyone who was ill. She did report smoking 3-5 cigarettes of the herb "Salvia" consistently for 3-4 months and quit approximately 48 hours before symptoms appeared. Her use of the herb had been consistent; she smoked several cigarettes each day. Laboratory results were essentially normal including the white blood cell count. She received symptomatic treatment and was released after one day. Discussion. Salvinorin A, a kappa-opioid receptor agonist, is the major active ingredient of S. divinorum. The unique opioid properties of this herb may explain its ability to cause changes in intestinal transit time. Conclusion. A 51-year-old woman possibly developed gastrointestinal manifestations suggestive of withdrawal from Salvia divinorum after smoking the substance consistently for 3 to 4 months. The widespread use of this herb will make the potential for withdrawal syndromes more commonplace.
PMID: 22611407 [PubMed - in process]

Opiate induced hyperalgesia

Is briefly reviewed in 

Singapore Med J. 2012 May;53(5):357-60.
Opioid-induced hyperalgesia: a review of epidemiology, mechanisms and management.
Low YH, Clarke CF, Huh BK.
PMID: 22584979 [PubMed - in process]

I found this most useful for it's list of citations. Note the NMDA system appearing again in this context.

Interestingly another authors proposes that tramadol may not be hyperalgesic due to effects at the noradrenalin and serotonin receptors

Antihypersensitivity Effects of Tramadol Hydrochloride in a Rat Model of Postoperative Pain.
Kimura M, Obata H, Saito S.
Background:Tramadol is used to treat a wide range of acute and chronic pain. This drug induces analgesia by 2 mechanisms of action: opioid receptor activation and enhancement of noradrenaline (NA) and serotonin (5-HT) transmission. The effect of tramadol on NA and 5-HT concentrations in the spinal cord, however, have not been assessed. In the present study, we investigated the antihypersensitivity effect of tramadol using a rat model of postoperative pain. We also evaluated the increase in NA and 5-HT levels in the spinal cord after tramadol injection using in vivo microdialysis.Methods:We made a hindpaw incision in male Sprague-Dawley rats (postoperative pain model). Tramadol was administered intraperitoneally and intrathecally 24 hours after paw incision. Mechanical hypersensitivity was measured by determining the withdrawal threshold using von Frey filaments. Microdialysis studies from the dorsal horn of the lumbar spinal cord were performed to measure NA and 5-HT levels after intraperitoneal injection of tramadol. We also measured the NA and 5-HT content in the spinal cord in normal rats and rats with paw incision.Results:Intraperitoneal (10, 20, and 40 mg/kg) and intrathecal (125, 250, and 500 μg) injection of tramadol produced an antihyperalgesic effect in a dose-dependent manner. The antihypersensitivity effect of tramadol was prevented by intrathecal pretreatment with methysergide (30 μg), a serotonin receptor antagonist; idazoxane (30 μg), a noradrenaline receptor antagonist; and naloxone (30 μg), a nonselective opioid receptor antagonist. Microdialysis study revealed that 5-HT and NA concentrations at the spinal dorsal horn were increased, peaking at 30 minutes after intraperitoneal injection of 20 mg/kg tramadol. Furthermore, the NA and 5-HT content in the ipsilateral dorsal half of the lumbar spinal cord was increased 1 day and 3 days after paw incision, respectively.Conclusions:These findings indicate that tramadol inhibits postoperative hypersensitivity by increasing NA and 5-HT levels in the spinal cord and activating opioid receptors. Tramadol might be more effective in the early postoperative period when spinal NA and 5-HT levels are increased.
PMID: 22575568 [PubMed - as supplied by publisher]

Cost of NAS care

JAMA in the May 9 issues http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2012.3951 notes that the incidence of NAS has tripled form 2000 to 2009 from 1.20 to 3.39 per 1000 hospital births per year.  The cost per infant was $53,400 in 2009 and average LOS was 16 days. 

"Newborns with NAS were significantly more likely to have respiratory diagnoses (30.9%; SE, 0.7%), to have low birthweight (19.1%; SE, 0.5%), have feeding difficulties (18.1%; SE, 0.7%), and have seizures (2.3%; SE, 0.2%)"  they do not differentiate women on maintenance treatment from those using illicit opiates at the time of birth.