Safety of epidural drugs: a narrative review

ABSTRACT

Introduction: Epidural analgesia is a popular approach to postoperative and labor pain. Neurotoxicity and drug-specific systemic side effects can occur after epidural administration. As an increasing number of epidural drugs are studied and clinically applied, drug efficacy and safety evaluation are crucial.

Areas covered: In this narrative review, the authors provide a thorough overview on the safety of the most widely used epidural drugs, focusing on potential neurotoxicity, side effects, and complications in the adult, non-pregnant population. A combined text and MeSH heading search strategy was used to identify relevant publications.

Expert opinion: The search for the ideal epidural medication has resulted in a surplus of drug combinations with extensive heterogeneity amongst studies, while the value of investigating these is not always evident. Epidural drugs pose a potential threat of neurotoxicity and other side effects. Consequently, we should pursue safe epidural drug administration to patients and refrain from drugs with minimal proven benefit. Also, studies should compare epidural with systemic application. Because why use a drug epidurally, which can be safely used systemically? Future research should focus on providing solid evidence regarding efficacy of epidural analgesia compared to new and already existing modalities and optimizing presently used medicinal regimens.

KEYWORDS:

• Epidural
• safety
• epidural drugs
• neurotoxicity
• systemic toxicity
• side effects
• drug efficacy
• safety evaluation
• neuraxial
• analgesia

1. Introduction

Epidural analgesia is a popular method for treating postoperative and labor pain, with over 3,7 million adult patients receiving epidural analgesia between 1998 and 2010 in the United States alone[1]. However, some concerns exist regarding epidural safety and efficacy. Observed severe complications, albeit rare, include epidural hematoma or abscess and neurological injury. Epidurally administered drugs have a higher potential for inducing neurotoxicity as compared to systemically. Hence, administering drugs systemically is the preferred route when efficacy is comparable to epidural application. In addition, drug-specific systemic side effects like hemodynamic instability or intoxication can also occur after epidural administration. In this narrative review, we aim to give a thorough overview on the safety of the most widely used epidural drugs, focusing on potential neurotoxicity, known side effects and possible complications of specific drug groups.

2. Search strategy

The search strategy is summarized in Figure 1. We included studies on epidural drug safety for perioperative analgesia in the adult, non-pregnant population, excluding papers on epidural drug safety in chronic pain, pregnant and pediatric patients. In addition, we included studies regarding systemic versus epidural drug efficacy. Medical Subject Headings terms used were, among others, epidural analgesia, local anesthetics, glucocorticoids, steroids, dexamethasone, bupivacaine, mepivacaine, lidocaine, opioid analgesics, buprenorphine, morphine, fentanyl, sufentanil, adrenergic alpha-agonists, epinephrine, clonidine, dexmedetomidine, ketamine, drug-related side effects and adverse reactions, hypotension and synonyms. Titles and abstracts were screened and cross-referenced for possible inclusion by MvZ, while when in doubt discussing eligibility with other authors (WtH, JH, MFS). Selected articles were restricted to articles in English, German or Dutch. Full text articles were retrieved and reviewed for all studies that seemed relevant and were assessed for eligibility.

Figure 1. Search strategy.

3. Local anesthetic

Local anesthetics (LA) are the main component in most epidural mixtures used in daily clinical practice. LA main site of action is a specific intracellular portion of voltage-gated sodium channels, which they block reversibly. The onset of action of LA is related to their pKa. A high pKa indicates a slow onset of action. Potency and duration of action of a LA, on the other hand, depend mostly on lipid solubility and protein-binding capacity: the more lipophilic the LA, the easier it diffuses across nerve membranes, increasing its potency. Increased protein-binding ensures LA are more tightly bound to the receptor sites and therefore dissociate more slowly [2] (see Table 1).

Table 1. Widely used local anesthetics.

Local anesthetic	Neurotoxicity[6]*	Cardiotoxicity[3]**	pKa	Lipid solubility	Protein binding capacity
Lidocaine	++	++	7.8[4]	+ [4,5]	++[4]
Bupivacaine	++	++	8.1 [4,5]	+++ [4,5]	+++ [4,5]
Levobupivacaine	++	++	8.1 [4,5]	+++ [4,5]	+++ [4,5]
Ropivacaine	++	++	8.1[5]	++ [4,5]	+++ [4,5]

* ++ = neurotoxic when increasing doses are administered.

**: – = no reported side effects; + = mild effect; ++ = moderate effect; +++ = profound effect.

3.1. Neurotoxicity

All LA have time- and dose-dependent neurotoxic properties [6,7] which correlate with their clinical potency [8]. Neurotoxicity is mediated through a variety of different mechanisms leading to apoptosis and necrosis [7]. Epidural neurotoxicity predominantly occurs after supra-clinical LA doses and therefore has little clinical impact in daily practice. Transient neurological symptoms (TNS) have been described after intrathecal LA administration, specifically lidocaine [9]. However, only one case report described TNS after epidural administration of lidocaine, and this was after a high dose (≥600 mg) was administered over a short (20 min) period of time [10].

3.2. Systemic toxicity

LA toxicity after systemic absorption of high doses of LA can produce central nervous system excitation with seizures, central nervous system inhibition, loss of airway reflexes, respiratory arrest, hemodynamic instability, and in extreme cases, coma or cardiovascular collapse. Case reports have shown possible benefit from the use of intravenous lipid emulsions in case of LA overdose [11], however its effect on lidocaine central nervous system toxicity has been debated [12].

In the sixties [13] the antiarrhythmic properties of lidocaine were described, which has resulted in its intentional intravenous administration in case of ventricular arrhythmias. In recent years, more widespread use of systemically administered lidocaine has been promoted as a possible alternative to epidural analgesia. Even high intravenous doses (up to 300 mg) of systemic lidocaine rarely give rise to problems like conduction disturbances or ventricular arrhythmias [14,15].

At equipotent dosing, all LA have similar toxic properties, however systemic LA toxicity after epidural injection is rare [16]. It has been suggested that ropivacaine has a superior safety profile compared to racemic bupivacaine. When given systemically to healthy volunteers, the tolerated maximum dosage of ropivacaine before start of neurotoxic and cardiovascular effects was twice as high as that of racemic bupivacaine [17,18]. Ropivacaine has a lower potency than both levo- and racemic bupivacaine and is approximately 10 times less lipophilic. At equipotent dose [19], it is uncertain whether there is really clinically relevant lower toxicity. Several cases in which intended epidural doses of ropivacaine were accidentally administered either intrathecally or intravenously resulted in severe complications [20,21]. Thus, whether ropivacaine actually has a safer clinical profile is questionable.

Finally, all LA can cause hypotension when administered epidurally. Increased hypotension after epidural LA administration, either with or without adjuvant opioids, was reported in two recent systematic reviews [22,23]. In both studies the incidence of hypotension was lower when a lower dose of LA was combined with an opioid, nonetheless it was still markedly higher than in the control group.

4. Opioids

Epidural opioids have been used for over three decades, after receiving their United States Food and Drugs Administrations (FDA) approval in 1984, with the first studies ranging back as far as 1979. Most epidural mixtures currently used combine a lipophilic opioid (fentanyl, sufentanil) with a long-acting LA (levo- or racemic bupivacaine, ropivacaine) because of their presumed synergism and the avoidance of delayed respiratory depression. A meta-analysis [22] suggested slightly better analgesic efficacy of epidural analgesia when compared with an intravenous pain regimen. A Cochrane systematic review supports this limited superior analgesic effect of epidural analgesia over systemic opioid administration in patients undergoing open aortic surgery, reporting a mean difference in VAS scores on movement on postoperative day 1 of −1.78 (95% CI −2.32 to −1.25) [24]. The clinical relevance of this difference is however debatable. According to the requirements for a clinically superior pain regimen of two points NRS reduction or 30% relative pain reduction from baseline recommended by the International Association for the Study of Pain (IASP), this difference cannot be seen as clinically superior.

4.1. Neurotoxicity

Nearly every opioid has shown at least some degree of neurotoxicity, including hydromorphone, tramadol, oxycodone, fentanyl, sufentanil and buprenorphine [25–35]. For neuraxial morphine, this is less consistent [26,36]. Researchers studying neurotoxicity of the DepoFoam technology, a lipid-based depot used for extended release morphine, deemed it safe [37] (see Table 2). Epidural nalbuphine [27] showed no neurotoxicity, but long-term clinical research regarding its safety is missing.

Table 2. Widely used epidural opioids.

Opioid	Neurotoxicity*	Notable side effects as epidural adjuvant**
Morphine	+[26,31]	Delayed respiratory depression +++[44,45] sedation +[38], hypotension +[38]
Morphine (extended-release)	+[26,31]	Delayed respiratory depression +++[47–52], sedation ++[54], hypotension ++[55]
Hydromorphone	+[25]	Delayed respiratory depression ++[59], sedation +[39], hypotension ++[39]
Fentanyl	+[35]	Sedation + [38,42,60], hypotension +[38]
Sufentanil	+[27]	Sedation ++[38,40], hypotension +[38]

*: – = no reported neurotoxicity; + = at least some reported neurotoxicity or inconclusive data;

++ = multiple reports, neurotoxicity probable; +++ = multiple reports, almost certainly neurotoxic

**: – = no reported side effects; + = mild effect; ++ = moderate effect; +++ = profound effect

It’s worth noting that very little neurotoxicity is reported in daily clinical practice, thus it can be assumed that the most frequently used epidural opioids (i.e. morphine, fentanyl, sufentanil) are safe when epidurally administered doses are in accordance with the current standard of care.

4.2. Systemic response and respiratory depression – hydrophilic opioids

Since the introduction of epidural opioids, it is well-defined that they all share, to some extent, the adverse effects as known from their systemic administration. These include, but are not limited to, hypotension, sedation, nausea, vomiting, pruritus, urinary retention and respiratory depression, whereby pruritus occurs more often after epidural opioid administration [41].

Morphine is one of the most frequently used opioids in epidural anesthesia. It has long-lasting analgesic effects, especially in combination with LA. Epidural morphine can produce delayed respiratory depression and it’s an ongoing discussion whether the respiratory depression is a result of its active metabolite morphine-6-glucuronide or because of the rostral spread of morphine in the cerebrospinal fluid into the brainstem [42]. It is worth noting that the pharmacokinetics of morphine seems to differ depending on the injection site (i.e. lumbar vs. thoracic catheter placement). This could result in a concentration gradient in the cerebrospinal fluid with concurrent alterations in the rostral spread, resulting in increased systemic side effects if similar doses of morphine are used in a thoracic relative to lumbar epidural [43]. Late respiratory depression has been found to occur up to 24 h [44] after an epidural dose. The incidence for delayed respiratory depression was found to be 0–2.8%[45], however a clear definition of respiratory depression is missing in the literature [45,46]. Older studies used larger dosages of epidural morphine and excluding those would result in a lower incidence.

The recently introduced extended-release variant of morphine should guarantee sufficient analgesia for up to 48 h, whilst simultaneously decreasing total opioid consumption. The sterile suspension of multivesicular liposomes contains morphine sulfate and works as a depot, ensuring a controlled release. After FDA approval in 2004, a high incidence (>10%) of adverse events, including respiratory depression, has been reported, especially after doses >15 mg [47–52], leading to the current-advised dose of ≤15 mg. Interestingly, this decreased dose resulted in less adverse events, but consequently also reduced the duration of action [53]. It has been debated whether it should be combined with LA because of potential physicochemical interactions which could alter the release of the morphine [54], triggering adverse effects like respiratory depression [55].

Hydromorphone is a hydrophilic opioid similar to morphine, but significantly more potent (for systemic action 1.5 mg hydromorphone equals 10 mg morphine). Its analgesic efficacy is comparable to epidural fentanyl, sufentanil [56] and morphine [57,58]. Delayed respiratory depression up to 4,5 hours after epidural drug administration at even modest dosages is reported [59] but seems to have a lower incidence than with morphine. Similar to morphine, an extended release preparation is available.

Many risk factors for delayed respiratory depression, like usage of hydrophilic opioids, advanced age, morbid obesity or obstructive sleep apnea, have been identified [45]. Considering these risk factors, the lowest clinically effective dose and adequate monitoring are essential for safe epidural usage of hydrophilic opioids.

4.3. Systemic response and respiratory depression – lipophilic opioids

For lipophilic opioids, the distribution to, and clearance from, the spinal cord and epidural space are rapid as compared to hydrophilic opioids, decreasing the risk of delayed respiratory depression when given epidurally [42]. Indeed, lower sedation levels and less respiratory depression are reported when comparing fentanyl to morphine [42,60]. Buprenorphine is a lipophilic long-lasting mixed agonist-antagonist. Its specific site of action is still unclear, but seems to be predominantly supraspinal of nature [61]. The use of epidural buprenorphine showed no advantages over epidural morphine [62]. Naloxone-resistant respiratory depression has been reported for epidural buprenorphine [63], but the incidence appears to be low.

4.4. Clinical implication

We suggest avoiding all widely used opioids that are proven neurotoxic and have no proven benefit when administered epidurally, being hydromorphone [64], buprenorphine [62] and tramadol [29,30].

Individual patient risk stratification is advised when using morphine and especially extended release morphine considering late respiratory depression. Dosing needs to be done carefully as adjustments cannot be made after administering the drug [51]. Because of its long duration of action, continuous monitoring for 24–48 h is recommended. Whether the risks of (extended-release) morphine outweigh its benefits remains to be seen.

Even though multiple studies have shown no added benefit for epidural sufentanil compared to its intravenous administration [65,66], it remains one of the most widely used adjuvants in epidural analgesia, presumably due to the LA sparing effect and thereby reducing the adverse effects of both drugs [67]. The use of epidural fentanyl and sufentanil appears safe when standard precautions for the use of opioids are taken. Because their mechanism of action is predominantly systemic [43], equianalgesic doses of intravenous lipophilic opioids are similar to epidural doses [65,66], compared to the much lower epidural doses of hydrophilic opioids necessary for equianalgesia.

In summary, none of the opioids reviewed show ideal epidural analgesic properties without any side effects. This does, however, not mean that there is no place for opiates in epidural anesthesia. The benefits of the synergistic LA/opioid mixture which result in less side effects are well established. Using the lowest effective dose and applying adequate monitoring should minimize complications.

5. Alpha-adrenergic receptor agonists

In recent years alpha-adrenergic receptor agonists have increasingly been used for epidural analgesia. Epinephrine as an adjuvant to LA is thought to decrease the clearance and distribution of LA from the epidural space. Intravenous clonidine and dexmedetomidine are known for their analgesic properties and, when administered epidurally, are thought to have an analgesic and LA sparing effect. Clonidine can be administered systemically, epidurally or intrathecally, because alpha2-adrenoceptors are localized throughout the central nervous system. Recent studies propose a predominantly spinal site of action suggesting neuraxial administration to be preferable over systemic clonidine for its analgesic effect [68,69]. When clonidine is administered epidurally, lower doses of LA and opioids can be used whilst still maintaining sufficient analgesia [70–72]. This dose-sparing effect could limit possible complications and adverse effects associated with the use of epidural LA and/or opioids. In contrast, oral clonidine similarly decreased epidural morphine dosages without any clonidine specific side effects [73]. This gives rise to the hypothesis that at least one extra pathway, apart from the spinal site of action, for clonidine’s analgesic properties exist. Oral administration of clonidine may reduce the required doses of epidurally applied drugs and medication-associated side effects to a similar extent as epidural clonidine.

5.1. Neurotoxicity

Safety concerns were initially issued regarding possible spinal cord ischemia after epidural epinephrine administration, however since then, studies in both animals and humans have debunked this [74]. Neurotoxicity or spinal cord ischemia in epidural use of epinephrine seems to be highly unlikely. Ambiguity remains regarding the safety of epinephrine in patients with an already compromised spinal circulation, where epidural epinephrine may perhaps aggravate already present LA-induced neurotoxic injury [74] (see Table 3).

Table 3. Epidural alpha-adrenergic receptor agonists.

Alpha-adrenergic receptor agonist	Neurotoxicity*	Notable side effects as epidural adjuvant**
Clonidine	-	Sedation+++[79,80], hypotension++[68,71,82], bradycardia++[68]
Dexmedetomidine	+[78]	Sedation+++ [75,81], hypotension++[75], bradycardia++ [75,81]
Epinephrine	-	-

*: – = no reported neurotoxicity; + = at least some reported neurotoxicity or inconclusive data;

++ = multiple reports, neurotoxicity probable; +++ = multiple reports, almost certainly neurotoxic

**: – = no reported side effects; + = mild effect; ++ = moderate effect; +++ = profound effect

Clonidine has been thoroughly studied in both animals and humans as an epidural adjuvant. Neurotoxicity seems to be low and epidural administration safe [76,77]. There is no consensus regarding the epidural neurotoxicity of dexmedetomidine and it is therefore currently not approved by the FDA [78].

5.2. Side effects

Common side effects of alpha-adrenergic receptor agonists include sedation, hypotension, and bradycardia. This resulted in discussions regarding its safety and the risk–benefit ratio for epidural administration. The adverse events reported for clonidine are dose dependent [79]. Similar to morphine, the systemic side effects increase when clonidine is given via thoracic epidural catheter, perhaps as a reflection of rostral spread [68]. Dexmedetomidine shares most of clonidine’s dose-dependent adverse effects [80], but displays a significant higher incidence of bradycardia and clearly increases sedation scores [81]. Pooled data did, however, not show any statistically significant increase in hypotension. Similar to clonidine less systemic opioids were needed.

5.3. Clinical implications

A recent systematic review concluded that the possible impact of adding epinephrine to epidural local anesthetics remains uncertain due to insufficient evidence. In addition, the side effects of clonidine and dexmedetomidine should prompt caution before using them as adjuvants in epidural analgesia, because even a low epidural dose of approximately 50ug/h of clonidine can cause considerable hypotension [68,71,82] care should be taken to assess and maintain hemodynamic stability in patients receiving clonidine.

Finally, more data from large comprehensive trials assessing long-term safety and efficacy of dexmedetomidine used as an adjuvant in epidural analgesia are necessary before recommending dexmedetomidine for neuraxial use.

6. Other frequently used epidural adjuvants

6.1. Dexamethasone

In 2014 the FDA issued a warning concerning the use of epidural steroids after a series of serious neurological problems including loss of vision, stroke, paralysis, and death [83,84]. Dexamethasone is a water-soluble steroid known for its analgesic, anti-inflammatory and antiemetic properties [85–87]. It is thought that water-soluble steroids like dexamethasone are safer than the more lipid soluble steroids like triamcinolone when given epidurally [88].

Multiple studies have emerged where dexamethasone has been used as an adjuvant to LA in epidural mixtures. The rationale for using dexamethasone epidurally was an assumed analgesic effect that was at least similar to other adjuvants, but with less side effects than other adjuvants like opioids or alpha-adrenergic receptor agonists [89]. To date, however, no studies assessed dexamethasone as the sole adjuvant to LA and comparing it to other LA/adjuvant mixtures.

Some researchers have deemed epidural dexamethasone safe. Nevertheless, safety issues still surround the use of epidural corticosteroids in general, and dexamethasone in particular [90,91] (see Table 4). For example, high (≥15 mg) doses of epidural dexamethasone were associated with transient adrenal suppression [92].

Table 4. Other epidural medication.

Other drugs	Neurotoxicity*	Notable side-effects as epidural adjuvant**
Dexamethasone	+++[97–101]	-
Ketamine	+++[102–104]	Sedation, psychoto- and sympaticomimetic effects +[93,94]
MgSO4	++[113–116]	-
Midazolam	+++[119–121,123]	Sedation+ [95,119,120] hypotension +[119,120]
Neostigmine	-	Sedation+[128]

*: – = no reported neurotoxicity; + = at least some reported neurotoxicity or inconclusive data;

++ = multiple reports, neurotoxicity probable; +++ = multiple reports, almost certainly neurotoxic;

**: – = no reported side-effects; + = mild effect; ++ = moderate effect; +++ = profound effect.

Very little is known about neurotoxicity of dexamethasone. The potential for neurotoxicity was not actively sought in the majority of the studies performed [96]. Water-soluble steroids have been implicated in seizures when given intrathecally [97–99] and higher doses of intrathecal dexamethasone were associated with increased inflammation of the subarachnoid space in rats [100]. In vitro, neurotoxicity was suggested when combining dexamethasone with ropivacaine [101].

6.2. Ketamine

Ketamine is a selective, non-competitive NMDA-receptor antagonist with known analgesic and in particular anti-hyperalgesic action. Evidence suggests that ketamine has neurotoxic properties when administered intrathecally [102,103]. Epidural ketamine should also be used with caution, especially when ketamine with preservatives is used. Particularly the well-known neurotoxic preservative benzethonium could worsen ketamine’s own neurotoxicity [104]. The added benefits of epidural ketamine over systemic ketamine are still debated [105,106], even though a small potentiating effect was seen when epidural ketamine was given in combination with morphine [107]. Systemic adverse reactions include psychotomimetic side effects and a mild sympathomimetic action, whereby the latter only occurs at plasma levels of >243 ± 54 ng/mL [93]. Considering the above, epidural ketamine should be reserved for very specific individual cases, for example, in palliative care. Only a few human studies assessed neurological complications [108] associated with the neuraxial use of ketamine and more data on its safety should be gathered.

Interestingly, ketamine had been advocated as an adjuvant for pediatric caudal anesthesia [109,110] based on a meta-analysis of 13 randomized controlled trials demonstrating its effectiveness [111]. However, doses used in those studies make a predominantly systemic analgesic effect likely. Thus, there is no evidence suggesting superiority of epidural over systemic application. There is considerable experimental data demonstrating neurotoxicity yet only one clinical study looked at permanent neurological damage. Therefore, neuraxial use of ketamine cannot be advocated.

6.3. Magnesium

Magnesium is a NMDA-receptor antagonist, similar to ketamine. The main reason for adding magnesium to an epidural drug-mixture is to reduce side effects of epidural LA and/or opioids, whilst assuring the same level of analgesia [112]. A high dose of magnesium intravenously (resulting in plasma levels >5 mmol/L) can produce flushing and hypotension that is not seen when applied via the epidural route, presumably due to a dose-dependent effect. Very high doses of magnesium resulting in plasma levels exceeding 6mmol/L could lead to hypermagnesemia, a potentially lethal condition.

Similar to ketamine, the main concern regarding neuraxial magnesium pertains to its neurotoxic potential [113,114]. Case reports in the obstetric population describe patients suffering from disorientation [115] or burning pain [116] following supra-clinical doses of magnesium accidentally given neuraxially.

6.4. Midazolam

Midazolam is a benzodiazepine acting on GABAA receptors thereby facilitating chloride influx into the cell resulting in neural inhibition. Midazolam showed some analgesic action when epidurally administered as an adjuvant to racemic bupivacaine [117,118]. Side effects for epidural midazolam are mainly sedation and hypotension, however, when using the lowest clinically effective dose of midazolam, those adverse events should be rare.

Neurotoxicity is a considerable concern and neurologic damage has been reported in animals when midazolam was given neuraxially [119,120]. Apoptosis induction is known to be mediated via the same mechanism as described for LA [121]. However, the quality of some animal studies reporting on neurotoxicity of midazolam has been questioned [122]. Therefore, no conclusive statement on the safety of neuraxial midazolam can be given. Worth mentioning, midazolam aggravated the neurotoxic properties of lidocaine [123]. Because all LA are neurotoxic [7], midazolam added to any mixture containing an LA could potentiate neurotoxicity.

6.5. Neostigmine

Neostigmine inhibits the enzyme acetylcholinesterase, thus interfering with the breakdown of acetylcholine in the synaptic cleft. Epidural neostigmine has shown, at best, doubtful efficacy. Some studies reported a dose-independent analgesic effect when combined with lidocaine [124]. Adding neostigmine to epidural morphine results in a longer time to first analgesic rescue medication, albeit, without a reduction in the total opioid consumption [125].

The main clinically relevant side effect for epidural neostigmine was significant hypotension [126], while nausea, vomiting, and sedation were also reported [127]. Epidural administration of neostigmine appears to be safe after extensive neurotoxicity research [123,128–130].

6.6. Clinical implications

When searching for a clinically useful epidural adjuvant, safety of the drug should have been proven and the epidural administration should have a clear beneficial effect. With this in mind, all adjuvants mentioned in the latter part of our review do not meet the aforementioned criteria. Epidural dexamethasone, ketamine, and midazolam are possibly neurotoxic and the analgesic efficacy of neostigmine or dexamethasone has not been well established. Potentially neurotoxic drugs should not be given epidurally, especially when systemic administration seems to work equally well.

Other epidurally used drugs like prilocaine, calcitonin or haloperidol fall beyond the scope of this review, due to a lack of appropriate studies.

7. Conclusion

As presented above, the optimal mixture for epidural analgesia does not exist. Consequently, individual patient characteristics, safety of the chosen medication (see Table 5), and a risk–benefit analysis should be leading in deciding which epidural medications to choose. Specific hospital safety measures should be in place before the application of epidural drugs in order to handle possible adverse events.

Table 5. Recommended safe doses* for commonly used epidural drugs in the adult non-obstetric population.

Drug (stand-alone therapy)	Safe hourly dose (continues infusion)	Maximal safe dose in 24 hours	Safe bolus dose	Drug (as adjuvant)	Safe hourly dose (continues infusion)*
Lidocaine	1,5 mg/kg/h[131]	2 g/24h**	4,5 mg/kg [138] (LE max. 500 mg/TE max. 300mg)[131]	Lidocaine	Not applicable
Bupivacaine	Max. 0.5 mg/kg/h[132]	400 mg/24h [132,133]	2.5 mg/kg[133]	Bupivacaine	Not applicable
Levobupivacaine	Max. 0.3 mg/kg/h**	400 mg/24h[134–135] **	2.5 mg/kg (max. 150 mg)[134]	Levobupivacaine	Not applicable
Ropivacaine	Max. 0.4 mg/kg/h**	800 mg/24h[136,137]	4 mg/kg (max. 250mg)[137]	Ropivacaine	Not applicable
Morphine	0.1–1.0 mg/h[139]	10 mg/24h[140]	2–5 mg[140]**	Morphine	0.1–0.2 mg/h[140]
Fentanyl	25–100 µg/h[139]	Variable	50–100 µg[141]**	Fentanyl	5–30 µg/h**
Sufentanil	X	Variable	10–30 µg**	Sufentanil	Max. 8 µg/h**
Hydromorphone	0.04–0.4 mg/h[142]	Variable	0.5–1.5 mg[142]	Hydromorphone	0.04–0.2 mg/h[60]**
Clonidine	0.1–0.4 µg/kg/h[143]** (max. 30-40ug)[143]	300 µg/24h**	0.1–0.4 µg/kg[143]** (max. 30-40ug)[143]	Clonidine	0.1–0.4 µg/kg/h[143]** (max. 30-40ug)[143]

* If multiple drugs are used in an epidural mixture all individual drugs should be dosed lower.

** Expert opinion: consensus by anesthesiologists in our University Hospital

LE: lumbar epidural; TE: thoracic epidural

When deciding on epidural medication, patient safety is most important. Whenever medication is dispensed close to the central nervous system it poses a potential risk for neurotoxicity or other adverse effects. If questions regarding drug safety are still unanswered or high-quality long-term studies have not unequivocally shown the safety of an epidurally administered drug, they should not be used in routine clinical practice.

Where most local anesthetics and some opioids clearly have their advantages when used in an epidural mixture, most adjuvant drugs described in this review have no or minor benefits when administered epidurally compared to alternative routes (mainly systemic administration). Especially drugs without any proven benefit when applied epidurally compared to their systemic administration should be avoided. Therefore, adjuvants beyond morphine, sufentanil, fentanyl, and clonidine cannot be advocated unequivocally.

Several relevant factors other than epidural drug safety, such as doses and side effects of systemic drugs, or the impact of a chosen analgesic regimen on patient outcome, fall outside the scope of this narrative review. However, in recent years many papers worth reading have been published addressing these issues [23,24,43,144,145].

8. Expert opinion

The search for new epidural medication seems never-ending and an abundance of research is dedicated to finding the optimal combination of drugs. This has resulted in an enormous amount of heterogeneous studies, which all study different mixtures in very specific groups of patients and procedures. Conclusive evidence regarding safety and efficacy is therefore difficult to interpret. There is a paucity of large randomized, multicenter, placebo-controlled studies for epidural drug usage. In particular, studies where the epidural adjuvant is compared to systemic administration are warranted. Furthermore, there are no large-scale prospective observational studies regarding the safety of frequently used epidural drugs.

In recent years regulatory oversight of clinical trials has greatly approved. It has become common practice to use multiple well-characterized animal models studying supra-clinical doses and concentrations of perineural drugs before administering them in humans. However, in rare cases, some epidural medications are still used experimentally without ensuring safety in humans. It sometimes seems minor advantages were weighed against perceivable, yet probably rare, deleterious neurologic outcomes.

Even if medication has thoroughly been tested, and no neurotoxicity has been shown in both animal and human studies, it still should be questioned whether it is necessary to administer these drugs epidurally. If a drug shows no added benefit when administered epidurally compared to intravenously, or when epidural efficacy is questioned, systemic administration should be preferred.

Our literature search focused on safety and efficacy of epidural drugs in non-pregnant adults. However, in vulnerable patient groups like pregnant women or children even more caution should be taken. The particularities of transplacental transport, teratogenic properties of drugs and increased neurotoxicity in a developing central nervous system should ensure even more precautions to be taken to avoid any possible harm.

Where in some fields, like obstetrics, the role of epidural analgesia is still widely accepted as the gold standard with regards to analgesic efficacy, the role of postsurgical epidural analgesia has somewhat diminished in recent years. Cumulative evidence supports the notion that there is no added benefit of epidural analgesia over a systemically administered pain regimen or peripheral/local nerve blocks (e.g. pre-peritoneal wound catheter [146]) for analgesic purposes for a growing number of perioperative indications.

Future research should focus on the risk–benefit analysis of epidural analgesia compared to new modalities and on optimizing presently used regimens rather than on fast-tracking the search for new epidural drugs. This is, in particular, true whenever basic safety issues have not been addressed properly.

This review has focused on the safety of epidural drugs. It is however important to keep in mind that other factors should be taken into account when using epidural analgesia. For instance, primary and secondary epidural failure rates are relatively high and minimally invasive surgical techniques, opiate sparing regimens and peripheral regional anesthesia, ranging from paravertebral blocks to pre-peritoneal or pre-pleural wound catheters, offer numerous options and alternatives to new experimental epidural drugs.

Article highlights

• Research regarding new epidural drugs and drug combinations is ever increasing.

• Clinically safe epidural usage of drugs should be pursued, reducing possible neurotoxicity and other side effects. In vitro and in vivo data can prescreen new drugs and drug combinations before administering them to patients, but only large-scale observational prospective studies looking for short- and long-term neurological change can demonstrate clinical safety.

• If there is no added benefit of administering drugs epidurally as compared to systemically, the systemic application should be preferred.

• The incidence of serious complications seems to be low, but the consequences can be devastating.

• Future research should focus on providing solid evidence regarding efficacy of epidural analgesia compared to new and existing modalities and optimizing established regimens.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Acknowledgments

The authors would like to thank Mrs. Faridi S. van Etten-Jamaludin, Clinical Librarian from the Medical Library of the Amsterdam UMC, location AMC for her assistance with building our search strategy.

Additional information

Funding

This paper was not funded.