Letter to the Editor

Can P-glycoprotein expression on malignant

tumor tissues predict opioid transport at

the blood-brain barrier in cancer patients?

Bruno Mégarbane1,2, Hisham Alhaddad1

�INSERM U705, CNRS UMR8206, Paris-Descartes University, Paris, France

�Medical and Intensive Care Department, Lariboisière Hospital, Paris-Diderot University, Paris, France

Correspondence: Bruno Mégarbane, e-mail: bruno-megarbane@wanadoo.fr

Key words:

analgesia, blood-brain barrier, buprenorphine, morphine, P-glycoprotein

Wang et al. investigated the analgesic effects of mor-

phine and buprenorphine in patients with histologi-

cally confirmed malignant tumors of different kinds at

terminal stages in one palliative care unit [12]. They

showed that patients with P-glycoprotein (P-gp)� tu-

mors required a higher morphine dose to achieve

a satisfactory analgesic effect assessed using the vis-

ual analog scale test, in comparison to patients with

P-gp� tumors. Following the infusion of higher mor-

phine amounts, patients with P-gp� tumors achieved

adequate analgesia. In contrast, patients exhibited

similar analgesic responses to buprenorphine, regard-

less of their tumor’s P-gp expression.

P-gp is a well-known ATP-binding cassette transporter,

encoded by the MDR1 (ABCB1) gene in humans. P-gp is

expressed in a variety of normal tissues, mostly of epithe-

lial origin, including at the luminal membrane of brain

capillary endothelial cells composing the blood-brain bar-

rier (BBB) and restricting brain parenchyma distribution

of its substrates by unidirectional efflux [9].

In Wang’s work [12], differences in the analgesic re-

sponse to morphine between patients with P-gp� and

P-gp� tumors were attributed to the P-gp-controlled

amounts of morphine reaching the brain across the BBB.

Consistently, P-gp is highly involved in the transport of

the majority of opioids at the BBB. As acknowledged by

the authors, morphine is a well-known P-gp substrate,

assessed in vitro and in vivo, either in animals or in hu-

mans. In contrast, buprenorphine is not a P-gp substrate

as recently demonstrated in vitro using human P-gp-

transfected cells [10] or placenta [7] and in vivo in mice

[2, 5], although one study suggested a possible P-gp

contribution to buprenorphine brain-to-blood efflux in

vivo in the rat [8]. Opioids are potent centrally acting

analgesics; however, the role of the increasingly recog-

nized peripheral opioid receptor system in the observed

difference in response to morphine between Wang’s

patients with P-gp� and P-gp� tumors cannot be ruled

out. Nevertheless, at the tumor level, the exact role of

P-gp in limiting morphine accessibility to its receptors

remains to be determined.

P-gp over-expression or up-regulation has been

recognized as contributing to the development of

resistance to chemotherapy in malignancies. Based on

their findings, Wang et al. stated that P-gp expression

in tumors may also be a valuable biomarker to predict

the individual analgesic response to morphine, assum-

ing its ability to predict morphine transport at the

BBB [12]. Prediction of the patient’s response to

P-gp-transported opioids and individualization of

drug therapy appears extremely interesting, especially

if simple tests become available for an easy screening

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of transporter expression at the BBB. However,

physiologically, P-gp expression is not co-ordinately

regulated in humans, making it impossible to consider

P-gp expression in one tissue as surrogate for another

[1]. Consistently, no correlation was found between

intestine and liver [11] as well as between intestine

and peripheral blood mononuclear cell expression of

P-gp [1, 3]. Moreover, significant dissociation has

been shown between P-gp expression level and activ-

ity in tumors [4], ruling out any definitive conclusion

regarding the consequences of P-gp expression on its

activity such as opioid transport.

To the best of our knowledge, no study has paral-

leled P-gp expression in the tumor and at the BBB in

the same individual. P-gp expression is modulated in

response to xenobiotics, stress, and diseases [1, 6, 9].

Increased expression has been reported in response to

signals that activate specific transcription factors in-

cluding pregnane-X receptor, constitutive androstane

receptor, nuclear factor-�B, and activator protein-1,

while reduced expression has been reported in re-

sponse to signaling through Src kinase, protein kinase

C and estrogen receptors [6]. Pro-inflammatory cyto-

kines have also been shown to be potent inhibitors of

P-gp. In Wang’s patients [12], P-gp expression at the

BBB and tumor levels may have been differentially

modulated by such factors including the response to

past chemotherapy and morphine administration.

Thus, in our opinion, due to patient heterogeneity,

limited data regarding cofactors that may have influ-

enced P-gp expression, and a debatable 10%-cut-off for

P-gp quantification on tissue slices, the clinical rele-

vance of Wang’s findings require further prospectively

designed studies before any definitive conclusion.

Conflicts of interest: None.

Funding sources: None.

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