Domperidone and ARVD

[Helen Marshall IBCLC]

I have a client who is considering starting Domperidone due to low milk supply however she has been reading all the information about the potential cardiac risks. She has a first cousin with ARVD and is concerned this puts her into a higher risk catergory. Her GP is also hesitant due to lack of information. Would you suggest an ECG before starting or is this not at all a risk factor?

Thanks

[admin]

Helen:

I do not know if there is any heritable risk of the arrhythmic syndrome in your patient (ARVD), I doubt there is however. That said, its not much trouble to get an ECG done to be certain she does not have a prolonged QT interval, which is what domperidone rarely precipitates.

My advice is to get a prolactin level first. If it is elevated ( > 70 ng/mL) then domperidone is a waste of time and won't work. If it is low (10-30 ng/mL), then domperidone may work. Keep the dose at 10-20 mg TID, and no more. This is all you need to stimulate prolactin levels into the milk producing range.

Good luck.

Tom Hale Ph.D.

[ginnawall]

Tom, has a research study ever been done to prove this, that "domperidone [or metoclopramide] is a waste of time and won't work"? In the RCTs studying placebo vs. galactogogue, researchers did not exclude subjects on the basis of their prolactin levels, and still found improvement in milk production. The way I read this is that, regardless of baseline, an increase in prolactin can and does help milk production. Also, what's the reference for ">70 ng/mL" and "10-30 ng/mL"?

[admin]

Ginna:

First, we know with certainty that domperidone and metoclopramide both stimulate milk production by increasing prolactin levels. Dozens of studies have confirmed this.
The dose-response studies of Wan and Knoppert below, clearly show that in women with low prolactin levels (10-20), that domperidone dramatically stimulates both steady-state plasma prolactin levels and milk synthesis.

The old study by Kauppila suggests that in patients who already have high prolactin levels, that metoclopramide will not increase plasma prolactin levels.

Further, we know that domperidone blocks the D2 receptor in the pituitary lactotroph, thus allowing the complete dumping of all prolactin from the pituitary. The elevated levels that subsequently occur over the ensuing hours, are basically steady state, or FLAT, but elevated at somewhere around 125-150 ng/mL. Thus the post-lactation "surge" goes away and is replaced by a steady, flat, sustained level of prolactin.

Peter Hartmann published years ago, that milk production is steady at about 750 cc/day in moms with a prolactin level of 150 ng/mL at 1 month to about 70 ng/mL at 6 months. All the subsequent papers on stimulating milk production in moms with low synthesis rate, have clearly shown that domperidone and metoclopramide dramatically work if the moms prolactin levels are in the 10-20 ng range.

No one that I have seen, has even shown an increase in prolactin levels occurring in moms who's levels are already HIGH. Thus I do not believe that domperidone is worth the effort to use in women with high prolactin levels. This is because multiple studies show a maxed out production in moms of around 150 ng/ml. That's all you can get without having a tumor. So giving domperidone or metoclopramide to a mom with high prolactin levels is a waste of effort.


Tom Hale, Ph.D.






Brouwers, J. R., Assies, J., Wiersinga, W. M., Huizing, G., & Tytgat, G. N. (1980). Plasma prolactin levels after acute and subchronic oral administration of domperidone and of metoclopramide: a cross-over study in healthy volunteers. Clin Endocrinol.(Oxf), 12(5), 435-440.
Brown, T. E., Fernandes, P. A., Grant, L. J., Hutsul, J. A., & McCoshen, J. A. (2000). Effect of parity on pituitary prolactin response to metoclopramide and domperidone: implications for the enhancement of lactation. J Soc Gynecol Investig, 7(1), 65-69. doi: S1071-5576(99)00048-9 [pii]
Bruera, E., Villamayor, R., Roca, E., Barugel, M., Tronge, J., & Chacon, R. (1986). Q-
Camanni, F., Genazzani, A. R., Massara, F., La Rosa, R., Cocchi, D., & Muller, E. E. (1980). Prolactin-releasing effect of domperidone in normoprolactinemic and hyperprolactinemic subjects. Neuroendocrinology, 30(1), 2-6.
Campbell-Yeo, M. L., Allen, A. C., Joseph, K. S., Ledwidge, J. M., Caddell, K., Allen, V. M., & Dooley, K. C. Effect of domperidone on the composition of preterm human breast milk. Pediatrics, 125(1), e107-114. doi: peds.2008-3441 [pii]
10.1542/peds.2008-3441
Campbell-Yeo, M. L., Allen, A. C., Joseph, K. S., Ledwidge, J. M., Caddell, K., Allen, V. M., & Dooley, K. C. (2010). Effect of domperidone on the composition of preterm human breast milk. Pediatrics, 125(1), e107-114. doi: peds.2008-3441 [pii] 10.1542/peds.2008-3441

Cox, D. B., Owens, R. A., & Hartmann, P. E. (1996). Blood and milk prolactin and the rate of milk synthesis in women. Exp Physiol, 81(6), 1007-1020.

da Silva, O. P., Knoppert, D. C., Angelini, M. M., & Forret, P. A. (2001). Effect of domperidone on milk production in mothers of premature newborns: a randomized, double-blind, placebo-controlled trial. CMAJ, 164(1), 17-21.


Ehrenkranz, R. A., & Ackerman, B. A. (1986). Metoclopramide effect on faltering milk production by mothers of premature infants. Pediatrics, 78(4), 614-620.

Ferrari, C., Scarduelli, C., Rampini, P., Brambilla, G., Benco, R., Pistolesi, E., . . . Crosignani, P. G. (1983). Prolactin response to the dopamine antagonists sulpiride and domperidone. Further evidence for pituitary dopamine deficiency in hyperprolactinemic disorders of different etiology. Gynecol Obstet Invest, 16(5), 299-306.

Gupta, A. P., & Gupta, P. K. (1985). Metoclopramide as a lactogogue. Clin.Pediatr.(Phila), 24(5), 269-272.

Hofmeyr, G. J., & Van Iddekinge, B. (1983). Domperidone and lactation. Lancet, 1(8325), 647.
Hofmeyr, G. J., Van Iddekinge, B., & Blott, J. A. (1985). Domperidone: secretion in breast milk and effect on puerperal prolactin levels. Br J Obstet Gynaecol, 92(2), 141-144.

Huizing G, Brouwers JRBJ, Westhuis P. (1980). Plasma drug concentration and prolactin release after acute and subchronic oral administration of domperidone and metoclopramide. . In M. F (Ed.), The serum concentration of drugs. (pp. 271-277). Amsterdam:: Excerpta Medica.

Ingram, J., Taylor, H., Churchill, C., Pike, A., & Greenwood, R. (2012). Metoclopramide or domperidone for increasing maternal breast milk output: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed, 97(4), F241-245. doi: 10.1136/archdischild-2011-300601
Kaufman, J. M., Elewaut, A., & Vermeulen, A. (1981). Effect of domperidone on prolactin (PRL)and thyrotrophin (TSH) secretion. Arch Int Pharmacodyn Ther, 254(2), 293-303.
Kauppila, A., Arvela, P., Koivisto, M., Kivinen, S., Ylikorkala, O., & Pelkonen, O. (1983). Metoclopramide and breast feeding: transfer into milk and the newborn. Eur J Clin Pharmacol, 25(6), 819-823.
Kauppila, A., Kivinen, S., & Ylikorkala, O. (1981). A dose response relation between improved lactation and metoclopramide. Lancet, 1(8231), 1175-1177.

Kiem, D. T., Nagy, G. M., Barna, I., & Makara, G. B. (1997). Domperidone stimulates prolactin secretion in rats with complete destruction of the mediobasal hypothalamus. Brain Res Bull, 44(2), 151-154.
Knoppert, D. C., Page, A., Warren, J., Seabrook, J. A., Carr, M., Angelini, M., . . . Dasilva, O. P. (2013). The effect of two different domperidone doses on maternal milk production. J Hum Lact, 29(1), 38-44. doi: 10.1177/0890334412438961

Livingstone, V., Blaga Stancheva, L., & Stringer, J. (2007). The effect of withdrawing domperidone on formula supplementation. Breastfeed Med, 2, 178.
MacDonald, T. M. (1991). Metoclopramide, domperidone and dopamine in man: actions and interactions. Eur J Clin Pharmacol, 40(3), 225-230.
Mancini, T., Casanueva, F. F., & Giustina, A. (2008). Hyperprolactinemia and prolactinomas. Endocrinol Metab Clin North Am, 37(1), 67-99, viii. doi: S0889-8529(07)00112-0 [pii]
10.1016/j.ecl.2007.10.013


Noel, G. L., Suh, H. K., & Frantz, A. G. (1974). Prolactin release during nursing and breast stimulation in postpartum and nonpostpartum subjects. J Clin Endocrinol Metab, 38(3), 413-423.

Wagner, C.L., Murphy, P.K., Haase, B., Barreira, J., & Taylor, S.N. (2011). Domperidone in the treatment of low milk supply in mothers of critically ill neonates [abstract]. Breastfeeding Medicine, 6.
Walsh, T. S., Foo, I. T., Drummond, G. B., & Warren, P. M. (1998). Influence of dose of domperidone on the acute ventilatory response to hypoxia in humans. Br J Anaesth, 81(3), 322-326.
Wan, E. W., Davey, K., Page-Sharp, M., Hartmann, P. E., Simmer, K., & Ilett, K. F. (2008). Dose-effect study of domperidone as a galactagogue in preterm mothers with insufficient milk supply, and its transfer into milk. Br.J Clin Pharmacol., 66(2), 283-289.

[ginnawall]

Thanks, Tom,

I'm so grateful for your quick response and the great collection of studies. I know some but not all of the studies and I'm looking forward to reading the ones I haven't read. But meanwhile I'm going to try to revive this dead horse

In Campbell-Yeo's 2012 study, subjects were recruited on the basis of their low milk production, not their prolactin levels. The researchers DID measure prolactin levels before and 14 days after starting domperidone/placebo. Prolactin mean (and SD) in the domperidone group on Day 0 was 72.1 (129.0), and on Day 14 it was 81.3 (70.8). In the placebo group on Day 0 it was 50.0 (41.7), and on Day 14 it was 36.0 (26.2). Breast milk volume increased in all but 2 women in the domperidone group within 48 hours of treatment initiation. The mean increase in breast milk volume in the domperidone group was 106% and in the placebo group it was 15%.

To me, this says that domperidone is worth a try, regardless of baseline prolactin levels.

[admin]

Ginna:

No one knows when these prolactin levels were drawn. During the surge, after the surge, or at trough. So its hard to know what their trough levels were.

But you get the point, that the lower the prolactin levels, the better Domperidone works. And I will continue to argue, that the higher the normal prolactin levels are, the less domperidone will work.

Tom