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Editorial
Goodbye to needles
  1. Brian J Anderson
  1. Correspondence to Professor Brian Anderson, Department of Anaesthesiology, C/- PICU, Auckland Children's Hospital, Park Road, Auckland 1023, New Zealand; briana{at}adhb.govt.nz

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By and large, children hate needles. Children in pain have a sympathetic response causing vasoconstriction rendering venous access somewhat more technically challenging than usual. Venous access in children presenting for anaesthesia is not always easy; nor is it always necessary for simple short procedures using inhalational anaesthesic agents. Similarly, children presenting to an emergency department with pain from a damaged limb require effective analgesia, and this can be delivered without resort to an immediate intravenous injection. Alternative routes for early analgesic administration are available. After all, adults commonly self-administer drugs with analgesic properties using mucous surfaces or the nasal cavity for recreational purposes. Neri and colleagues1 describe their own positive experience using sublingual tramadol and ketorolac.

The oral route of drug administration is a stalwart for elective procedural sedation. There are often time delays before the drug is absorbed in the small intestine, and further delays before the drug in plasma reaches its site of action. The latter is commonly known as the effect compartment, and it is drug concentration in this effect compartment that correlates with response rather than drug concentration in the plasma. Sedative and analgesic administration can be timed to take advantage of absorption characteristics, therapeutic effect compartment concentrations or metabolites. Ketamine, for example, is reported satisfactory for dressing changes in children suffering burns. Formation of its metabolite norketamine after oral absorption is advantageous because it also has analgesic properties, but for many drugs, the oral route is less than ideal in the emergency room. Pain relief is desired reasonably quickly. Trauma may cause delayed gastric emptying, slowing delivery and absorption in the small intestine. Paediatricians have known the value of alternative routes, such as the rectum, for decades; rectal diazepam is still used for seizure control. It is rapidly absorbed with peak concentrations at approximately 16 min. Rectal diclofenac, a non-steroidal anti-inflammatory drug (NSAID), is also readily absorbed rectally and provides good analgesia for those whose oral intake is restricted or unavailable in the perioperative setting. Unfortunately, not all drugs have such good bioavailability or absorption characteristics when administered by the rectal route. Paracetamol is slowly absorbed with a bioavailability of only 60% that of elixir, and peak concentrations may not be attained until 1–2 h after administration. Peak effect compartment concentrations are even later.2 Delayed absorption of rectal morphine has contributed to respiratory arrest in infants. Cultural beliefs may also count against suppositories.

Exploration of alternative delivery routes in young children has mostly centred on the nasal passages, and the nasal route for opioid delivery is gaining popularity in children. Nasal diamorphine 0.1 mg/kg is used in the UK for forearm fracture pain in the emergency room.3 Nasal sufetanil and ketamine have also been used for paediatric analgesia, but for much of the world fentanyl remains popular for acute and chronic tuning of pain control. Nasal fentanyl (150 mcg/mL) 1.5 mcg/kg given to children (3–17 years) for fracture pain resulted in good analgesia. The pain score (visual analogue scale 0–100) was reduced from 80 mm (IQR 60.0–95.5) to 49.5 mm (IQR 26.5–68.5) at 10 min and 27.5 mm (IQR 18.5–56.5) at 20 min.4 Similar results are reported for nebulised fentanyl (4 mcg/kg) given through a standard nebuliser. Adult studies using a pectin-based gelling agent that modulates fentanyl absorption while limiting nasal drip or runoff are promising. This formulation is proving useful for controlling breakthrough pain in adult cancer patients.

There are always concerns about respiratory depression with opioid use. Consequently, alternative non-opioid analgesics, such as the NSAIDs and tramadol, are increasingly explored. Improved nasal delivery systems provide dosing accuracy. Administration of ketorolac15 mg (weight <50 kg) or 30 mg (weight >50 kg) by the intranasal route using a metered spray resulted in a rapid increase in plasma concentration (time to peak concentration was 52 SD 6 min) and may be a useful therapeutic alternative to intravenous injection in adolescents because plasma concentrations attained with the device are likely to be analgesic. A target concentration of 0.37 mg/L in the effect compartment was achieved within 30 min and remained above that target for 10 h.5

Buccal and sublingual administration in children have generally been considered unsatisfactory because drugs require prolonged exposure to the mucosal surface. Younger children find it difficult to comply with instructions to hold a drug in their mouth for the requisite retention time (particularly if taste is unfavourable), and this results in more swallowed drug or drug spat out, than in adults. Bioavailability of an oral transmucosal fentanyl formulation was lower than that in adults, suggesting that many children (3–11 years) swallowed a large fraction of the dose.6 Buccal and sublingual administration, where there is considerable drug swallowed, results in lower plasma concentrations if that drug has a high first-pass effect because bioavailability is reduced.

However, Neri and colleagues have demonstrated a reasonable analgesic effect with both the NSAID ketorolac and tramadol. In fact, pain reduction for these drugs given sublingually in children 4–17 years was similar to that described for the powerful synthetic opioid, fentanyl, when administered nasally. These results are very encouraging. The sublingual route for analgesia appears a valid alternative to improve analgesia for children in the emergency room. Like the nasal route, it offers ease of administration, rapid systemic absorption and avoidance of hepatic first-pass metabolism. The scourge of strong opioids (nausea, vomiting, respiratory depression) is avoided with NSAIDs. Unfortunately, tramadol is still associated with nausea and vomiting, and this has been demonstrated again by Neri and colleagues.

The paper by Neri and colleagues entices further research questions, the answers to which may improve the benefits of the sublingual route for analgesic drugs (ketorolac, tramadol) and others. It would be nice to know the absorption characteristics (relative bioavailability, absorption rate constant) so we can determine the time of maximum effect. Effect is related to the concentration in the effect compartment, and the delay between peak concentration in the plasma and that in the effect compartment can be characterised by the equilibration half-life parameter (T1/2keo), which is approximately 24 min for adults given ketorolac. Consequently, once absorption characteristics are known, then the time of maximum effect can be estimated. It would also be useful to know concentration–response relationships for these drugs because it is possible that bigger doses may confer increased benefit. Smaller doses may be associated with fewer adverse effects, such as nausea and vomiting. Because the concentration–response relationship for either the beneficial or adverse effects of tramadol remain unknown, it is difficult to know where to pitch the dose. Some idea of the desired concentration in the effect compartment (eg, ketorolac 0.37 mg/L, tramadol 0.3 mg/L) will allow manipulation of the dose that achieves that concentration (figure 1). Knowledge of variability within both the pharmacokinetics (eg, time-concentration profiles) and pharmacodynamics (concentration-effect profiles) and the contributors to that variability may improve dosing in individual children. It may also be that drug combinations may show benefits over single drug therapy. Sublingual formulations containing two drugs are yet to be explored. The use of an enteral NSAID combined with paracetamol is now common practice; improved analgesia can be gained with smaller doses of each drug when used in combination. Lastly, we ignore taste at our peril. Children will not retain the drug under the tongue unless the taste is satisfactory. While nasal midazolam may remain popular for rapid short-duration sedation before anaesthesia, the acrid taste means that there is no gentle second administration if the first dose is ineffective. Surveillance of any new administration route designed to improve children's care is of course mandatory.

Figure 1

Ketorolac time-concentration profiles, and 90% prediction intervals for a child (age 15 years, weight 55 kg) given ketorolac 30 mg intranasally. Possible effect compartment concentrations were determined using a T1/2keo of 24 min. The concentration in the effect compartment associated with satisfactory analgesia in half the patients (EC50) is shown as a dotted line. Similar information for the sublingual route is desired to improve dosing using that route. (Adapted from Drover et al4).

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Footnotes

  • Competing interests None.

  • Provenance and peer review Commissioned; internally peer reviewed.

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