A 62 year-old Chinese gentleman with hepatocellular carcinoma
secondary to chronic hepatitis B infection and
metastases involving the peritoneum and abdominal
wall presented with generalized pruritus of 2 months duration.
The pruritus was generalized and particularly severe at night,
resulting in insomnia. Physical examination revealed hepatomegaly
with a large nodule over the right hypochondrium.
There were scattered excoriations over his body but no primary
dermatosis or asteatosis was observed.
Laboratory investigations revealed mildly elevated levels of
aspartate aminotransferase (43 U/L [15-33U/L]), alkaline phosphatase
(122 U/L [32-103U/L]) and gamma-glutamyl transferase
(223 U/L [13-63U/L]). Alanine aminotransferase (31U/L [7-36U/
L]) and serum bilirubin levels were normal (23 umol/L [5-30]).
Parameters of the synthetic function of the liver were also normal,
with albumin levels of 39g/L (37-51g/L), prothrombin time
(PT) of 10.9s (9.2-11.2s), and activated partial thromboplastin
time (aPTT) of 27.5s (27-36.1s). Computed tomography of the
abdomen and pelvis revealed multiple heterogeneous masses
in both lobes of the liver, with peritoneal nodularity suggestive
of peritoneal involvement. The patient was started on emollients,
topical corticosteroid therapy, oral anti-histamines, and
phototherapy with narrow band ultra-violet B light therapy.
However, he did not experience any relief of his symptoms. Due
to the intractable nature of his pruritus, the patient was started
on oral naltrexone 50 mg per day. He did not experience any
side effects and his itch score on a combined visual analogue
and numerical scale decreased from 6/10 pre-treatment to 2/10
after three weeks of treatment. The relief in itch was sustained
until 10 weeks later when he cut down the dosage to 25mg per
day and subsequently stopped taking it altogether due to the
high cost of naltrexone. The itch started recurring after he cut
down the dosage. With subsequent reinstatement of naltrexone
at 50mg per day, his symptoms again abated.
Paraneoplastic itch is defined as itch that occurs early during
the natural process or even precedes the clinical evidence of
the malignancy, is not caused by the neoplastic mass invasion
or compression and subsides after the removal of the tumor.
The common prototype of paraneoplastic itch is the pruritus of
lymphoma, which can often precede the other clinical signs by
weeks and months. Paraneoplastic itch has been anecdotally
reported in solid tumors of different types and the severity can
range from mild to intractable.
The pathophysiological mechanisms of paraneoplastic itch are
poorly understood. In pruritus caused by hepatobiliary tumors,
cholestasis from tumor compression of the draining bile ducts
is often the cause. However, this was not the case in our patient
as the bilirubin levels remained normal. He also had normal parameters
of the synthetic function of the liver (albumin, PT, and
PTT), indicating that his pruritus was not due to the accumulation
of pruritogenic toxins from hepatic dysfunction.
Intense, generalized itch is one of the most common side effects
of mu-opioids such as morphine. Though the role of endogenous
opioids has not been studied in the setting of paraneoplastic itch,
clinical and experimental observations have demonstrated that
pruritus can be evoked or intensified by both endogenous and
exogenous opioids. This suggests that opioids may have a role
to play in both systemic and chronic itch.
The mechanism by which opioids mediate pruritus is thought to
be related to their inhibition of the opioid-sensitive interneurons
that connect itch and pain neurons. It is generally postulated that
the mu-opioid system induces itch whereas the kappa-opioid
system suppresses itch. Both Mu-opioid receptor antagonists
(MORAs) and kappa-opioid receptor agonists (KORAs) have
demonstrated efficacy in chronic and systemic pruritus.
Treatment options for paraneoplastic itch tend to be limited
with variable efficacy. Some of the options include selective
serotonin reuptake inhibitors (SSRIs) in lymphomas and solid
carcinomas, mirtazapine in lymphoma, thalidomide in Hodgkin
lymphoma and psoralen plus ultraviolet A (PUVA) in cutaneous
T-cell lymphoma. Most of the supporting data for these therapies
is based on case series or small-scale studies and focuses
mainly on the treatment of paraneoplastic itch secondary to
lymphomas rather than solid tumors.
The efficacy of MORAs has been demonstrated in several randomized
control trials in the treatment of cholestatic pruritus, chronic
urticarial, and atopic dermatitis. In case series and reports, MORAs
were also noted to have efficacy in prurigo nodularis, mycosis
fungoides, post-burn pruritus, aquagenic pruritus, hydroxyethyl
starch-induced pruritus and pruritus of unknown origin. To our
knowledge, this is the first reported case of the use of naltrexone
in the treatment of paraneoplastic itch from solid tumors.
In this case study, naltrexone was efficacious and safe in the
treatment of paraneoplastic itch secondary to metastatic hepatocellular
carcinoma. Its efficacy suggests that endogenous opioids
may have an important role in the pathogenesis of this condition.
All authors have no relevant conflicts to disclose.