**8. Opioids**

information, clinicians can refer to neuropathic pain guidelines that provide evidence‐based recommendations for specific disease state‐induced neuropathic pain [29]. If acute or chronic pain is completely neuropathic in nature, the WHO's stepwise ladder is not appropriate to

After the addition of nonopioids and possible adjuvants, the WHO's analgesic ladder calls for low to strong opioids. However, if a patient is in severe acute pain, it is reasonable to start therapy with all three types of analgesics and then rapidly de‐escalate to a lower step on the analgesic ladder [9]. When treating chronic pain, opioids should never be utilized as first‐line agents outside of cancer or palliative care. Opioids have only been shown in the literature to have a short‐term improvement in pain and carry a high risk for serious side effects and possibly even death [6]. Before initiating therapy, clinicians and patients should have a dis‐ cussion regarding expected goals and potential risks. Goals should include how efficacy will be measured for both pain relief and functionality and what measures will indicate contin‐ ued treatment. Patients should also be informed that opioids only show a short‐term benefit in relieving pain and long‐term efficacy is lacking. Expectations should be that opioids will

The addition of opioids to a chronic pain regimen should be considered carefully. Patients do not need to fail nonopioids or adjuvants prior to initiating opioids, benefits must simply out‐ weigh the risks of starting opioid therapy [1, 8]. Another way to consider this is that opioids should be considered in patients with severe disabling pain that is likely not to be relieved from nonopioids and adjuvants alone. The worst risks are with overdose and potentially fatal respiratory depression. Overdose risk is dose dependent, and clinicians should be care‐ ful when doses are escalated. This is particularly important as there is technically no ceiling dose for opioids. Several other factors increase the risk for opioid‐related overdose including methadone use, co‐prescription with benzodiazepines, history of sleep‐disordered breathing, reduced renal or hepatic function, increased age, pregnancy, history of substance abuse and psychiatric illness. Additionally, the risk of opioid‐related overdose is elevated when starting patients on opioid therapy with long‐acting or extended release formulations. For this reason, these dosage forms should only be utilized in opioid‐tolerant patients. Risk mitigation strate‐ gies such as checking prescription refill history, urine drug screening and use of medications specifically for opioid use disorders (methadone, buprenorphine) increase retention in opioid

Prior to starting opioid therapy, the prescriber must fully understand the concepts of opioid abuse (opioid misuse disorders), tolerance and physical withdrawal [6]. Opioid abuse or opioid misuse disorders are described by patterned misuse of opioids that include unsuccessful attempts to curb use and results in social problems at home, work or school. Tolerance is simply a diminished response to a fixed dose of medication with repeated use. Physical dependence is when a medication causes the body to change in a way that when the medication is removed the body produces withdrawal symptoms. Both

follow and a medication regimen targeting neuropathy should be initiated.

**7. Risk of opioids**

194 Pain Relief - From Analgesics to Alternative Therapies

likely never provide complete relief.

treatment programs.

It is believed that opium was cultivated in Mesopotamia as early as 3400 BC [35]. Natural occur‐ ring opiates are the alkaloid compounds found in the poppy plant and include morphine and codeine while the term opioid refers to any compound that binds to opioid receptors. Narcotic originally was used to describe a medication that causes sleep, but the common misuse of drugs like quaaludes and barbiturates along with opioids caused this to become an umbrella term for drugs that are commonly abused. It is even used in a legal sense to describe the drugs of abuse. Even though opioids are grouped together, they have a wide range effects and each medication has unique properties (**Table 2**). There are four major opioid classes, and understanding each of the groups allows for easier prescribing as efficacy and side effects are similar within classes.



**Table 2.** Properties of common opioids.

originally was used to describe a medication that causes sleep, but the common misuse of drugs like quaaludes and barbiturates along with opioids caused this to become an umbrella term for drugs that are commonly abused. It is even used in a legal sense to describe the drugs of abuse. Even though opioids are grouped together, they have a wide range effects and each medication has unique properties (**Table 2**). There are four major opioid classes, and understanding each of the groups allows for easier prescribing as efficacy and side effects are similar within classes.

> **Starting oral dose (mg)**

30 30–60 Immediate release:

7.5 4–8 Immediate release:

10 5–10 Immediate release:

20 15–30 Immediate release:

– 0.025 Transdermal: 24

4–6

8–24

200 30–60 4–6 Only available in

4–6

12–24

30 5–7.5 4–6 Only available in

4–6

12

4–6

12

Extended release:

Extended release:

Extended release:

Submucosal:

Extended‐release:

**Dosing interval (h) Comments**

Several different extended‐release formulations each with their own dosing interval recommendations Strong opioid

combination with paracetamol Weak opioid

Several different extended release formulations each with their own dosing interval recommendations Strong opioid

combination with paracetamol Weak opioid

Strong opioid

Can use lower starting doses if using combination product with paracetamol Weak opioid (combination product) Strong opioid (when used alone at higher doses)

Use only in patients suffering from severe chronic pain

**Equianalgesic oral dose (mg)**

**Drug name pertinent dosage forms**

> release extended release (Ms contin and kadian)

196 Pain Relief - From Analgesics to Alternative Therapies

release (combination with paracetamol)

release Extended release

release (combination with paracetamol)

release Extended release

release (alone and combination with paracetamol) Extended release

Submucosal

Morphine Immediate

Codeine Immediate

Hydromorphone Immediate

Hydrocodone Immediate

Oxymorphone Immediate

Oxycodone Immediate

Fentanyl Transdermal;

The phenanthrenes are one of the larger classes of opioids and contain the prototypical opioid morphine. This class contains the most commonly used opioids including morphine, codeine, hydrocodone, hydromorphone, oxycodone, oxymorphone, levorphanol, buprenorphine, nal‐ buphine and butorphanol [35]. A majority of these agents are metabolized in the liver by the CYP450 isoenzyme CYP2D6. Some even require metabolism to exert analgesic effects. For example, codeine itself has no analgesic effect in its original state, and it is only through metabolism by CYPD6 to morphine that it can produce an analgesic effect [36]. A similar process happens to both hydrocodone and oxycodone to be converted to hydromorphone and oxymorphone. Similar to codeine, hydrocodone has been proposed to be a prodrug and its analgesic effect is dependent on activation by CYP2D6. Oxycodone, on the other hand, is a μ‐opioid agonist and does not require activation by CYP2D6. A serious issue arises with the fact that CYP2D6 has a very dramatic range of activity from one person to the next. It has been reported in literature that through a mutation, some patients have no activity of CYP2D6 (codeine produces no analgesic effect) whatsoever while others may be classified as ultrar‐ apid metabolizers. This may explain the wide range of reported efficacy in patients who are prescribed codeine‐ and hydrocodone‐containing products.

Another common attribute of drugs in the phenanthrene class is that they are typically gluc‐ uronidated and eliminated via the kidneys. This is especially important for morphine whose glucuronidated metabolite, morphine‐6‐gucuronide, is responsible for its analgesic effects [37]. In young and healthy individuals, this is not of importance, but in elderly or those with markedly reduced renal function, morphine's analgesic effects are prolonged. Morphine prescribed at fixed intervals in this patient population should be closely monitored as the respiratory side effects may accumulate as the medication is cleared more and more slowly. Additionally, drugs in this class with a 6‐hydroxyl group (morphine and codeine) are associ‐ ated with a higher incidence of nausea than those in the class that do not [35].

Phenlyperidines include the agents' fentanyl, alfentanil, sufentanil and meperidine. Of these, fentanyl has the highest affinity for the μ‐opioid receptor and is 80–100 times that of mor‐ phine [35, 37]. While incredibly potent fentanyl has a very short half‐life leading to a short duration of action. Fentanyl's only advantage is that is highly lipophilic leading to its ability to be utilized nontraditional dosage forms. One of these dosage forms is the transdermal patch. Fentanyl transdermal patches should only be used in the most extreme cases of chronic low back pain. This dosage form possesses many nuances, and a complete understanding of them should be obtained before prescribing. When a fentanyl transdermal system is placed on a patient, it takes 6–12 h before taking effect [37]. Additionally, it will take 3–6 days to reach steady state and when removed a reservoir of drug will remain in effect up to 24 h. This makes initiating and weaning incredibly difficult and therefore should not be commonly done. Fentanyl also has a submucosal dosage form that may be beneficial in patients who suf‐ fer from acute breakthrough pain. The clinically applicability of this makes sense because of fentanyl's high potency and short duration of action. It is important to stress that this should not be prescribed on a regular basis and should only be utilized as a rescue medication in very rare cases. The majority of patients with chronic low back pain should not be prescribed fentanyl, but in rare circumstances, it may have clinical utility.

The other opioids in the phenlyperidine class should not be used in the treatment of low back pain. Meperidine is a relatively weak opioid agonist with poor oral absorption that fell out of favor due to its neurotoxic and anticholinergic side effects [23, 37]. Its metabolite normeperidine accumulates in patients with renal insufficiency and lowers seizure threshold. Additionally, it has significant drug‐drug interactions with monoamine oxidase inhibitors that lead to severe respiratory depression. The other agents that are sufentanil and alfentanil in this drug class have little to no role in the treatment of low back pain due to their short duration and lack of specialized dosage forms.

The remaining classes of opioids consist of the benzomorphans and the diphenylheptanes. The only agent in the benzomorphan class is pentazocine, which is a mixed opioid agonist‐ antagonist. The diphenylheptaines include propoxyphene and methadone. While metha‐ done has established itself in a highly specific role, propoxyphene has fallen out of favor dramatically [16]. Propoxyphene is thought to be no more efficacious than paracetamol, and it has a plethora of side effects. It has been associated with dizziness, weakness, paradoxical excitement, falls, visual disturbances and insomnia [35]. Propoxyphene itself is thought to act directly on the central nervous system and increase the risk for seizure activity which ulti‐ mately leads to the product being pulled off the market in the United States.

Several opioids have mixed agonist‐antagonist activity and have only a limited role in the treatment of pain. These drugs provide small analgesic effects in patients with little or no prior opioid exposure and may exacerbate withdrawal symptoms in patients who have a physical dependence on opioid medications [35, 37]. Drugs in this group are pentazocine, butorphanol and nalbuphine. These agents have a ceiling effect on both analgesia and respiratory depres‐ sion and have limited abuse potential. As doses escalate so do the antagonistic effects against other opioids. This places the patient at risk for withdrawal. Also, the risk for psychotomi‐ metic side effects (delirium, delusions and hallucinations) increases in conjunction with the dose [37]. Pentazocine has the highest incidence of these side effects. The role of these agents in pain is limited by their antagonistic effects and lack of convenient dosage forms. Only pentazocine is available in an oral dosage form and has fallen out of favor to treat acute or chronic pain. The partial agonist buprenorphine acts similarly to the agonist‐antagonists with the one caveat that it is not associated with psychotomimetic side effects. Similar to the ago‐ nist‐antagonists, it can produce withdrawal symptoms when administered to patients taking high doses of other opioid medications. It is also combined with naloxone to reduce the risk of abuse. Buprenorphine is available as a sublingual dosage form in the United States and a transdermal extended release system in Europe. The sublingual form is commonly used in the United States in addiction treatment programs.

Phenlyperidines include the agents' fentanyl, alfentanil, sufentanil and meperidine. Of these, fentanyl has the highest affinity for the μ‐opioid receptor and is 80–100 times that of mor‐ phine [35, 37]. While incredibly potent fentanyl has a very short half‐life leading to a short duration of action. Fentanyl's only advantage is that is highly lipophilic leading to its ability to be utilized nontraditional dosage forms. One of these dosage forms is the transdermal patch. Fentanyl transdermal patches should only be used in the most extreme cases of chronic low back pain. This dosage form possesses many nuances, and a complete understanding of them should be obtained before prescribing. When a fentanyl transdermal system is placed on a patient, it takes 6–12 h before taking effect [37]. Additionally, it will take 3–6 days to reach steady state and when removed a reservoir of drug will remain in effect up to 24 h. This makes initiating and weaning incredibly difficult and therefore should not be commonly done. Fentanyl also has a submucosal dosage form that may be beneficial in patients who suf‐ fer from acute breakthrough pain. The clinically applicability of this makes sense because of fentanyl's high potency and short duration of action. It is important to stress that this should not be prescribed on a regular basis and should only be utilized as a rescue medication in very rare cases. The majority of patients with chronic low back pain should not be prescribed

The other opioids in the phenlyperidine class should not be used in the treatment of low back pain. Meperidine is a relatively weak opioid agonist with poor oral absorption that fell out of favor due to its neurotoxic and anticholinergic side effects [23, 37]. Its metabolite normeperidine accumulates in patients with renal insufficiency and lowers seizure threshold. Additionally, it has significant drug‐drug interactions with monoamine oxidase inhibitors that lead to severe respiratory depression. The other agents that are sufentanil and alfentanil in this drug class have little to no role in the treatment of low back pain due to their short

The remaining classes of opioids consist of the benzomorphans and the diphenylheptanes. The only agent in the benzomorphan class is pentazocine, which is a mixed opioid agonist‐ antagonist. The diphenylheptaines include propoxyphene and methadone. While metha‐ done has established itself in a highly specific role, propoxyphene has fallen out of favor dramatically [16]. Propoxyphene is thought to be no more efficacious than paracetamol, and it has a plethora of side effects. It has been associated with dizziness, weakness, paradoxical excitement, falls, visual disturbances and insomnia [35]. Propoxyphene itself is thought to act directly on the central nervous system and increase the risk for seizure activity which ulti‐

Several opioids have mixed agonist‐antagonist activity and have only a limited role in the treatment of pain. These drugs provide small analgesic effects in patients with little or no prior opioid exposure and may exacerbate withdrawal symptoms in patients who have a physical dependence on opioid medications [35, 37]. Drugs in this group are pentazocine, butorphanol and nalbuphine. These agents have a ceiling effect on both analgesia and respiratory depres‐ sion and have limited abuse potential. As doses escalate so do the antagonistic effects against other opioids. This places the patient at risk for withdrawal. Also, the risk for psychotomi‐ metic side effects (delirium, delusions and hallucinations) increases in conjunction with the

mately leads to the product being pulled off the market in the United States.

fentanyl, but in rare circumstances, it may have clinical utility.

duration and lack of specialized dosage forms.

198 Pain Relief - From Analgesics to Alternative Therapies

Methadone is another opioid with a unique mechanism of action other than being a μ‐opioid receptor agonist. This mechanism may be particularly advantageous for patients who have "opioid‐resistant" pain states or have a neuropathic component to their pain [37]. Similar to some of the agents to treat neuropathy, the R‐isomer of methadone is antagonistic at the NMDA receptor and may be beneficial in treating the effects of hyperalgesia and allodynia seen in chronic pain states [37]. Methadone should be used with caution as mentioned before its use increases the risk for overdose and a misunderstanding of its pharmacokinetics and pharmacodynamics perpetuates this effect. The terminal half‐life of the drug is typically thought to be 15–60 h, but has been cited as up to 120 h [38]. Because of this, it may take a week or longer to reach steady state, and therefore, the drug should be titrated no more often than weekly. Additionally, the analgesic effect of methadone is roughly 4–8 h and should be dosed on an every 8‐h interval. Due to this discrepancy, the drug has a high risk for accumu‐ lation and may put the patient at risk for sedation, confusion, respiratory depression, cardiac abnormalities and death. The general consensus is that a dose of 2.5 mg every 8 h is a safe starting dose for opioid‐naive patients [38]. Careful monitoring should be performed on any patient starting on methadone. Another caveat to dosing methadone is that it has a nonlinear equianalgesic conversion. This means that patients on higher doses of opioids are more sen‐ sitive to the effects of methadone and when converting the ratio of morphine equivalents to methadone dose decreases. However, with caution, the practitioner can utilize this effect to their advantage in treating the most complicated of patients.

Lastly, there are two agents that are sometimes considered opioid analgesics, but have both opioid and nonopioid mechanisms. These two agents are tramadol and tapentadol. While both have activity at the μ‐opioid receptor, this activity alone does not equate to the full analgesic effects seen with these agents [35, 39]. The remainder of their analgesic effects can be attributed to the inhibition of serotonin and norepinephrine reuptake. Similar to TCAs, this may be useful in treating neuropathic pain and caution should be used when combining therapy with other antidepressants or medications that increase the levels of serotonin as it increases the risk for serotonin syndrome [29]. Tramadol can be used for mild‐to‐moderate pain, but it should not be used as monotherapy when opioids are indicated based on the severity of pain. Tramadol's analgesic effect is at most equal to codeine and is probably less than that of hydrocodone [13, 16]. The maximum dose of tramadol is 100 mg every 6 h. Higher doses than 400 mg a day should not be used as it increases the risk for lethargy, nausea, tachy‐ cardia, agitation and hypertension. Additionally, tramadol has a neuroexcitatory effect so as doses increase so does the risk for seizures [13]. For these reasons, tramadol should be used either as an adjuvant medication or prior to stepping up to moderate or strong opioid‐con‐ taining regimens and is often seen as adjunct medications.
