Reversal of
opioid-related
respiratory depression is often accompanied by an "acute abstinence like syndrome" with
hypertension,
tachycardia, and
pain. This overshoot was used to investigate the extent at which
opioids of high potency but different structure are involved in
naloxone-induced abstinence. In 10 awake and trained mongrel dogs two highly mu-selective compounds,
alfentanil and
fentanyl, were given in cumulative doses and at different occasions (30-60-120-240 micrograms/kg, and 6-12-24-48 micrograms/kg, respectively). Subsequently, a high dose of
naloxone (100 micrograms/kg) was given at 5 min intervals while arterial blood
gases, blood pressure, heart rate and the somatosensory evoked potential (SEP) were measured continuously. Following a wash-out period, the 19-isoamyl derivative of
etorphine (
M-140; 10,000 times more potent than
normorphine and a 4.5 fold potency of
ethylketocyclazocine in a bioessay preparation) was also given in increasing doses (0.2-0.4-0.8-3.2 micrograms/kg). Again,
naloxone was given (100 micrograms/kg) at 5 min interval, while cardiovascular parameters, blood
gases and SEPs were measured continuously. All three
opioids induced a dose-related
respiratory depression with hypercarbia and
hypoxia, a dose-related
bradycardia, and a modest
hypotension. This was accompanied by a dose-related depression of the amplitude of the SEP, reflecting the degree of blockade of nociceptive afferents.
Naloxone was sufficient to reverse respiratory impairment after
fentanyl,
alfentanil and
M-140. However, in contrast to
fentanyl and
alfentanil, there was no cardiovascular or evoked potential overshoot following
naloxone reversal of
M-140. After
alfentanil naloxone increased blood pressure, heart rate and amplitude of the SEP by 7%, 41% and 38%, respectively. After
fentanyl this increase in blood pressure, heart rate and amplitude of the SEP was 17%, 43% and 96%, respectively. The study indicates that the more potent the
opiate mu
ligands are the more is
naloxone liable to induce a hyperexcitatory state of the cardiovascular system and an increase of nociceptive stimuli to
pain modulating centres. After
M-140 reversal of mu-related
respiratory depression by
naloxone was possible. However, no precipitation on an acute abstinence-like syndrome affecting antinociception or inducing cardiovascular overshoot was observed. This may stem from an intense binding and slow dissociation of the
ligand from the receptor site or may be due to high binding affinity to both the mu and the
kappa receptor site.
Opioids which interact with various receptor sites may be of clinical interest for substitution
therapy in
opioid dependent addicts.