Direct effect of four different compounds on experimental pain

Treatment of acute pain after surgery and chronic pain in cancer patients
consists of many different modalities. Apart from various types of
non-pharmacological interventions, most often therapy consists of
administration of analgesics. However, in the past several non-analgesic
compounds have been used in the perioperative setting to decrease postoperative
pain sensation and therefore faster postoperative recovery and hospital
discharge. Other substances have proved usefull in the treatment of metastatic
bone pain en phantom limb pain. These products are known as adenosine,
dexamethasone, zoledronic acid and salmon calcitonin.

Although these products have been used extensively in patients, the effect of
these medications on experimental pain sensation has never been investigated.
There is little knowledge about any direct effect of these medications on pain
perception. In the following study we want to investigate whether such a direct
analgesic effect in experimentally provoked pain exists.

Placebo-controlled, double-blind, randomized, cross-over study.

Volunteers will be randomly assigned to either first placebo group and a couple
of weeks later treatment group or vice versa. All volunteers will undergo in
total two series of pain tests: one treatment session and one placebo session
in random order. The subjects will be unaware in which session they are
participating.

A thermal stimulus will be applied on the volar side of the forearm of the
participant. This may produce a short lasting red discoloration of the skin
which will disappear in a couple of hours.

The administration of the substances is accompanied by several side-effects:

Adenosine
The most common side effects associated with the administration of adenosine
include flushing, chest discomfort, bronchospasm and dyspnea, headache,
gastrointestinal discomfort, bradycardia, AV-block and lightheadedness. Most of
these effects are generally well tolerated and transient due to the short half
life of the product (estimated to be less than 10s). Administration of the drug
should occur under continuous monitoring of cardiac rhythm. In case a second or
third degree AV-block develops, the administration of adenosine should be
discontinued immediately.

Zoledronic acid
The use of zoledronic acid may be accompanied by headache, diarrhoea, nausea
and vomiting. Furthermore bone pain, joint pain and muscle pain have been
described as well as hypocalcemia. Very occasionally osteonecrosis of the jaw
has been reported. This condition is more likely to develop after repeated
infusion schemes. The intravenous use of bisphosphonates may be regularly
associated with an influenza type of syndrome, characterized by bone pain,
fever, fatigue and muscle rigidity.

Dexamethason
When given too rapidly, dexamethason may cause a perineal flushing reaction.
This effect may be related to the phosphate buffer rather than the drug itself.
Usual glucocortioid side effects include gastrointestinal bleeding, impaired
wound healing, increased blood glucose levels, and increased susceptibility to
infection. These side effects are usually only seen in patients receiving
steroids on long-term basis. Apart from these regular side effects, also
insomnia and agitation have also been described, especially when given in the
setting of postchemotherapy nausea prophylaxis.

Salmon calcitonin
During salmon calcitonin administration, facial flushing, nausea, vomiting,
light sedation and dizziness may be observed. Twenty to thirty mins after
infusion flushing of the face and chest may be seen. 4-6 hours after
administration a predominantly asyptomatic hypocalcemia may develop.