Sublingual analgesia: a promising proposal for the treatment of pain

KEYWORDS:

• Analgesia
• pain treatment
• sublingual
• opioids

1. Introduction

The effective, safe and timely management of acute pain is critical. Other than the obvious benefit of reduced suffering, the earlier administration of pain treatment is associated with earlier discharge from the Emergency Department (ED) [1], improved post-operative functionality, less development of chronic pain, and a reduced incidence of post-traumatic stress disorder [2]. While oral opioids (PO) are generally recommended over parenteral opioids [3] there are limited alternatives for the noninvasive management of pain. There are times when a patient may need pain treatment more rapidly than can be achieved with oral opioids or require an agent that is not effective when given PO, but when intravenous (IV) access is either not yet available or otherwise not indicated. In these situations, the sublingual route of administration may offer a useful alternative.

Titrating opioids is most easily done using the IV route. Placing an IV, however, can be painful, time consuming, and the fail rate for the first attempt is 12–26% in adults [4], and in some situation IV access is limited. While most severely ill patients need an IV, some patients in moderate or severe pain may not otherwise need one or will require an unknown amount to time to get an IV due to situations complicating access. Accessing veins can be difficult in acute settings such as the Emergency Department, especially in patients who are obese, elderly, have burns, or are needle-phobic. Obesity is the number one reason for difficult IV access in the ED. Needle phobia has been reported in 14–38% of patients [5].

Oral medications have a slow onset. The onset of pain relief from oral medications has been described as around 30 minutes [6], but it is highly variable depending on a wide variety of factors. In addition, most of the opioids that are effective for PO administration are associated with active metabolites, which can complicate the treatment of patients due to variable accumulation and elimination. The variation in onset and elimination can complicate the titration of PO medications, limited their safe and effective use in severe pain or in dynamic situations of progressive pain symptoms.

In between IV titration and PO opioids, there are limiting options for acute pain treatment. Intramuscular medications are painful, and the onset is unpredictable, especially in patients with perfusions deficits. Nasal administration has been described for a variety of opioids, but the use is limited by wide variations in efficacy. There are, however, some sublingual opioids available for use that is some cases bridge some of the gaps between IV and PO opioid administration.

1.1. The sublingual space

The sublingual mucosa is the most permeable region in the oral cavity. While the buccal mucosa is comprised of 40–50 cell layers and is 500–800 um thick, the sublingual mucosa has fewer cell layers and is 100–200 um thick [7]. Compared to the gingival mucosa, the sublingual mucosa is nonkeratinized, which makes it more permeable to medications. The thin, non-keratinized mucosa of the sub lingual space makes it the optimal place in the oral cavity for trans mucosal drug administration.

The lipophilicity of a drug determines whether it can permeate the epithelial cell membranes, while the intercellular permeability is determined by a drugs hydrophilicity. Sublingual drug absorption involves a combination of these two mechanisms, but lipophilicity is the main determinant of a drugs sublingual potential. A drug’s pKa is an important determinant of its lipophilicity in the oral cavity. The normal pH of saliva is 6.5, but it can vary due to a variety of factors including mouth breathing, eating, or drinking, which can all affect a drugs trans mucosal absorption [7].

Another important factor in the sublingual administration of medications is that it bypasses hepatic first pass metabolism, improving bioavailability for some drugs relative to the oral route.

Finally, due to the limited volume and surface area of the sublingual space, potency is also an important aspect determining a drug’s utility for sublingual administration. These factors make drugs such as morphine, oxycodone, and hydromorphone, which are strongly hydrophilic and not potent relative to other opioids, have limited utility relative to more potent and lipophilic opioids such as fentanyl, sufentanil, methadone, and buprenorphine for sublingual use.

2. Available sublingual analgesics

There have been a variety of investigations into various sublingual opioids for pain (Table 1). Most of them have been in the setting of the treatment of breakthrough pain from cancer. Opioid tolerant patients are better able to tolerate variations in the plasma level of drug than opioid naïve patients, so the safety of sublingual opioids has been more easily established in these patients than in opioid naïve patients. Sublingual opioids for acute pain have generally not been well described in non-cancer breakthrough pain, with the exception of sufentanil [8–12]. The described onsets of pain relief are all defined differently in the available research, with some listing the first time the patient was reassessed and others the time at which any relief was detected, making comparisons between agents and studies difficult. The analgesic effect is also highly variable among the various studies, due both to variations in measurement techniques and in the actual detected effect due to the variations in adsorption in sublingual dosing, especially in studies describing the hydrophilic less potent agents like morphine and oxycodone.

Table 1. Sublingual opioids [7,10,14,17,18].

Medication	Equivalent dose	Time to onset	Bioavailability
Sublingual Morphine	15 mg	30 minutes	Variable, ranges from 10–61%
Sublingual Oxycodone	10 mg	30–60 minutes	20%
Sublingual Sufentanil	30 mcg	15 minutes	53%
Sublingual Fentanyl	100 mcg	5–15 minutes	76%
Buccal Fentanyl	100 mcg	5–15 minutes	54%
Intranasal Fentanyl	100 mcg	7 minutes	89%
Sublingual Burepnorphine	0.4 mg	15–30 minutes	55%

2.1. Fentanyl

Fentanyl is an opioid agonist indicated for the management of acute severe pain. Its half-life is 30–45 minutes. Unlike many opioids, it has no active metabolites. It is used in a variety of formulations. IV Fentanyl is frequently used because of its fast onset (<1 minute), lack of active metabolites, and relatively short duration of action that allows repeat patient assessments. That same benefit is also its limiting factor, since it requires frequent repeat dosing. It is ineffective as a PO medication due to its high first pass metabolism. IM and subcutaneous fentanyl have a slower and more variable onset (8–30 minutes) and are difficult to titrate, limiting their usefulness relative to typical PO opioids.

Fentanyl sublingual spray [13,14], buccal tablets [15], and sublingual tablets have all been described for the management of breakthrough pain in cancer patients who are already tolerant to opioid therapy for their underlying persistent pain. They have onsets described as 7–15 minutes but are described at doses that are generally too high for use in non-opioid tolerant patients. The short duration of fentanyl means that multiple doses are needed to treat pain, which lead to variable and increasing plasma concentrations, which is better tolerated in opioid tolerant patients [13,14].

Fentanyl has been described for use intra nasally using an atomizer and with a nebulizer [16] using the IV formulation in acute non-cancer pain. This approach has been noted to have an onset of 7 minutes and a duration of action 45 minutes, with a variable analgesic effect. While sublingual fentanyl results in effective pain treatment, its safe use in non-cancer pain has not been well explored for use outside of urgent situation without other options.

2.2. Sufentanil

Sufentanil is an injectable and sublingual opioid agonist indicated for the management of acute severe pain [10]. It is only administered in a monitored healthcare setting. Sufentanil is a highly lipid soluble compound that results in a very fast onset of action and a very fast distribution after IV administration. Its half-life is 2.5 hours. Unlike many opioids, it has no active metabolites. When given IV, the Cmax is initially very high, resulting in frequent apnea when administered IV to non-intubated patients, limiting its use as an IV opioid generally to intubated patients in the operating room. When administered sublingually, the Cmax is 17x lower than IV sufentanil, eliminating this effect and making the drug suitable in more situations [17].

The recommended dose of sublingual sufenatanil is 30 mcg. This dose may be repeated every hour for up to 72 hours. It is administered under the tongue using a single dose applicator. Patients should be instructed to refrain from eating or drinking for 10 minutes after administration. Ice chips may be administered if the patient complains for excessive dry mouth. This medication should only be given in a monitored setting and isn’t indicated for outpatient use [10–12].

Several studies of this medication have found significant pain relief at 15 minutes increasing until 60 minutes after administration [10–12]. With adverse events like other opioid medications. Nausea was reported in 29%, headache in 12%, vomiting in 5%, dizziness in 5%, and hypotension in 4% [10]. Currently, it is the best described sublingual opioid for use in acute pain in opioid naïve patients.

Sublingual sufentanil is also used in patient-controlled analgesia (PCA). It has been described as having similar efficacy to PCA morphine with a dose of 15 ug with a 20-minute lockout [9].

2.3. Morphine

Early studies comparing PO and sublingual morphine were largely equivocal (onset 30 minutes, with variable bioavailability complicating dosing) [7]. It is likely that morphine is not very well absorbed, resulting in its slow and variable onset.

2.4. Oxycodone

Oxycodone is generally the gold standard of PO opioids. The studies of sublingual oxycodone, however, have a bioavailability of 20%, which is far worse than PO oxycodone. This could be increased to 70% if the saliva is alkalinized. It is unlikely that SL oxycodone is more effective than PO oxycodone, and the variation due to salivary pH makes it probably less predictable in its effect.

2.5. Buprenorphine

Buprenorphine is a partial u-opioid agonist with K-receptor antagonist properties, used frequently to treat opioid addiction. It is very lipophilic and generally well absorbed (~50%) It has shown to be effective sublingually for analgesia, but its slow onset and long offset may its effectiveness for the treatment of acute pain [18].

3. Expert opinion on the role of sublingual opioids

Very few studies have found more than a statistical significance in pain relief onset between oral and sublingual medications. Much of this is likely due to limitations in the measurements used in pain research, but the difference is probably with the range of 10–15 minutes, which is probably only a significant amount of time in episodes of severe acute pain, such as acute trauma, when even a ‘statistical difference’ in pain relief more quickly might be important for the patient. It is more likely that sublingual medications have a larger role in allowing the use of agents that have benefits in a patient but don’t have an IV option (like sufentanil), or when an IV could be avoided but PO medications aren’t indicated or are inadequate.

When a patient requires immediate pain relief, and there is no IV available, the sublingual route of administration is an effective way to provide pain relief. Sometimes, giving a PO medication may be sufficient, especially when a patient is in only moderate pain and a difference in the time of pain relief of only 10–15 minutes is not critical. But in some patients, such as in patients with fractures, burns or other traumatic injuries presenting with acute pain, achieving some pain relief when IV access is delayed may be of tremendous benefit to the patient.

Similarly, some patients don’t need an IV other than to receive pain medications, or are difficult to get access on, or afraid of needles, but aren’t a good candidate for PO medications. The common PO opioids; morphine, oxycodone, and hydrocodone, all produce significant breakdown products that make for variable effects, durations of actions, and predispose some patients to adverse events. This is most common among elderly patients and leads us to often choose opioids without active metabolites, such as fentanyl, which cannot be given PO and lead to having to use an IV. The sublingual option could avoid this, but further studies are needed to determine the safety of sublingual fentanyl in conditions other than cancer breakthrough pain, leaving sufentanil as the only agent available in these situations.

Placing an IV can be difficult and time consuming, and it’s likely that there are a variety of situations when an IV opioid is needed, but the patient could otherwise get by without an IV. Examples include an elderly patient with a non-displaced hand fracture in severe pain, or a patient who had their IV pulled after day surgery but now has increased pain. Using a sublingual medication in these settings, and avoiding placing an IV, decreases the amount of work done to care for the patient and allows for their more efficient treatment. In one study, it was found that when measured from the time of the order, PO oxycodone had a faster time to pain relief than IV morphine. It is likely that this would be even more pronounced if sublingual opioids were used [6].

Sufentanil has not been typically used outside of the operating room and isn’t usable in typical pain treatment as an IV drug due to its high Cmax. As a sublingual drug, however, patients can get the benefit of its lack of breakdown products, plus its longer duration of action than fentanyl. This combined with its low Cmax relative to therapeutic levels and low adverse event rates that have been described make it a very promising agent for the treatment of acute pain in situations when an IV isn’t available or otherwise needed and an opioid without active metabolites is needed.

In the coming years, further research will be needed to more firmly establish the safest doses of sublingual opioids in opioid naïve patients, and to establish the range of peak onsets of sublingual opioids to allow for their safe titration. As the knowledge develops, titrating sublingual opioids for acute pain could become an important part of pain management, decreasing both the dependence on IV administration and the use of agents with active metabolites in patients unlikely to tolerate them.

Declaration of interest

J Miner has received grant support from AcelRx Pharmacueticals and has been a paid consultant to AcelRx Pharmacueticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.