Intranasal Opioid Spray for Postoperative Pain Relief

In collaboration with the Department of Pharmacy (Mr CB Lim and Mr M Roberts) we are continuing studies of the absorption and effectiveness of nasal opioids.

Currently this is hydromorphone, which is relatively cheap and works for some time. Doses are given both intravenously and nasally after major gynaecological surgery.

The nasal spray device we use has been developed locally and provides a suitable fixed volume of spray of droplet size most likely to assist absorption and prevent irritation of the nose and loss of liquid into the throat. Two different formulations of hydromorphone are being investigated, one of which contains a substance from shellfish that is known to help the nasal absorption of some other drugs.

The Safety of Drugs used during Breastfeeding

Tramadol is a new and strong pain-relieving drug that is widely used to treat moderate to severe pain. After caesarean section, tramadol is now often prescribed, especially on the third day, about when breast milk production is increasing. The only study looking at whether tramadol passes into breast milk investigated a single dose, so it has not been possible to completely reassure women that there will be no effect on their breast-fed baby.

In conjunction with UWA Pharmacologists, we are studying women already receiving tramadol after caesarean section, and measuring the amount of tramadol and its main breakdown compound in their blood and breast milk. By quantifying the concentration of tramadol in milk and maternal blood, and carefully assessing the breastfed infants, we can accurately assess the relative infant dose and the likelihood of significant adverse effects in the baby. This study of 75 women is nearing completion, and analyses show that tramadol has low and acceptable levels of transfer into human milk.

Caesarean Section - Improving Methods of Pain Relief

We have recently completed a clinical trial in collaboration with the Department of Obstetrics, investigating the effect of magnesium on pain after caesarean section. Magnesium is commonly given during pregnancy, especially to prevent seizures. One of its actions is in the spinal cord where pain signals are processed, so we were interested both in possible relief of postoperative pain and in prevention of long-term wound pain.

This study evaluated 120 women, assigned to intravenous magnesium or placebo at the time of surgery. Unfortunately, magnesium did not reduce pain or the need for morphine-like opioid drugs, and appeared to increase blood loss.

We are now about to start two new studies of pain relief after Caesarean section. One will compare two "patient-controlled" methods of pain relief. Women will receive the opioid fentanyl, either through an epidural catheter placed before surgery or by means of a nasal spray. This will allow us to compare the effectiveness of the nasal fentanyl with an established epidural method that is known to provide excellent pain relief. We will also measure the amount of fentanyl absorbed from each site of administration.

The second study is designed to look at the infusion of a new local anaesthetic, levo-bupivacaine, into the wound at caesarean section. This method is suitable following general or spinal anaesthetic, when there is no epidural catheter in place. We expect that the infusion will reduce the amount of opioid required after the operation, or possibly reduce pain severity. The secondary aim of the study is to measure the absorption of the local anaesthetic, so that a safe rate of infusion can be estimated.

Does Pethidine and/or Local Anaesthetic Solution in the Abdominal Cavity Reduce Pain after "Key-Hole" Surgery?

We have just completed a 3-year study designed to determine whether pethidine, with or without local anaesthetic, relieves pain after major “key-hole” surgery, when instilled into the abdominal cavity at the end of a laparoscopic operation. Instilling local anaesthetic has a beneficial effect on pain after minor laparoscopic surgery, for example sterilisation. Pethidine might work because it is absorbed into the blood (thus being similar to the effect achieved after an injection into a muscle or intravenous “drip”) or by acting as a local anaesthetic on the operated area.

We studied 220 patients having either laparoscopic cholecystectomy at Royal Perth Hospital or major pelvic gynaecological laparoscopy at King Edward Memorial Hospital. They received a solution into the abdominal cavity at the completion of surgery, that contained either pethidine (two different doses), local anaesthetic, both, or a placebo (these patients also received an injection of pethidine). Unfortunately, in contrast to the effect after laparoscopic sterilisation, there was no benefit from either local anaesthetic or pethidine. This may be because the surgery was more extensive, involving injury of deeper tissue. Pethidine was quite quickly and well absorbed, such that the peak plasma concentration was approximately half that of an equivalent intramuscular dose.

How Much Blood should be Injected for a “Blood Patch”?

The most effective treatment of headache, caused as a complication of an epidural or spinal block, is to insert an epidural needle and to inject the patient’s own blood, as a ‘patch’. The volume of blood recommended has increased from 2-3 ml in the 1960s, 10 ml during 1970-1990, 15-20 ml in the 1990s to ‘as much as possible’ recently. This suggests no-one really knows! I designed a multinational, multicentre, randomised trial to address what volume of blood might be most appropriate.

The study has recruited 30 of 120 obstetric cases to date, and involves maternity units in Australia, Canada, the USA, Belgium, and New Zealand, with more expected to participate soon. It is hoped to complete the study in 12-18months.

Less Sickness after Anaesthesia and Surgery

We have had a long-standing research interest in the prevention of nausea and vomiting, having completed a number of studies over the past decade, including a large study of 620 day-surgical patients last year. This study determined the optimal dose of two highly effective drugs, dexamethasone and ondansetron.

Currently, we are participating in a multinational, multicentre study of a new type of anti-nausea and anti-vomiting drug. This drug has been found to be useful in preventing sickness from chemotherapy, so is being investigated for its effectiveness against postoperative nausea and vomiting.

Novel Drugs for Pain Relief

The processes involved in how we experience pain are exceptionally complex, from the nerve ending through the spinal cord to the brain. Many new drugs are being developed to target different sites, nerve transmitters and receptors. One group of drugs being used to treat chronic pain, where injury to nerves is involved, includes a new investigational drug under development, but not yet available on the market. There is some evidence that its predecessor, originally designed as an anti-epileptic drug, also has some activity in relieving acute pain (for example, from injury or surgery).

We have designed a study, approved by the parent pharmaceutical company in the USA, to look at the effectiveness of this drug for postoperative pain. We have chosen as a model for such pain women having uterine procedures. Although not recognised as being painful surgery, we have found that many women do experience moderate to severe cramping pain, of the type most likely to be responsive to this type of drug.

Dreaming after Anaesthesia

About 1 in 6 patients recovering from surgery report that they have been dreaming. Dreaming is more common in younger patients. Some dreams suggest that the patient may have been lightly anaesthetised, but it is not known if the depth of anaesthesia correlates with the incidence of dreaming.

In the “Genie” study, we are monitoring the patient’s depth of anaesthesia (using a new monitor called a BIS monitor) and then observing the frequency and nature of dreams they report in the first 4 hours. This should provide information as to whether depth of anaesthesia is of relevance and allow new hypotheses to be formulated.