**3.6 Adjuvants, co-analgesics: systemic and topical**

Antidepressants and anticonvulsants have been used as systemic adjuvants for chronic pain and neuropathic pain. Number needed to treat (NNT) and number needed to harm (NNH) was adapted from Finnerup et al. in 2005 and 2007. Topical adjuvants include lidocaine patch and capsaicin and ointment and topical formulation with certain local anesthetic, amitriptyline, ketamine, gabapentin, and clonidine have been reported as beneficial for localized pain which is neuropathic in nature [27, 28].

#### *3.6.1 Opioid analgesics*

Chronic pain management requires opioids, we need to consider pain diagnosis, risk/benefit of use of opioid in an individual, mental health and behavior. Opioid risk tool has been useful to note the risk and if it is high, consider goals and boundaries, verbal or written signed documents to encourage patient's better behavior [18] (**Table 1**).


#### **Table 1.**

*Opioid use requires goal setting and needs to be shared with the patient, the first time and reminded on follow-up.*


**Table 2.**

*High risk in a patient with opioids or substance and opioid use disorder likely, consider boundary setting and improving behaviour.*


#### **Table 3.**

*Long-term opioid use can activate glia and immune cells causing tolerance, allodynia, and hyperalgesia and considering how to approach pain management.*

Opioids use has been common, and morphine was considered as a "gold standard" for pain management few decades ago along with "no ceiling". Initially, morphine was used for acute pain when the pain was excessive and Twycross, once he was able to establish physiological half-life of morphine, suggested every 4 h, and on the clock. In the early 1980s and before, opioids were short-acting oral pills, liquid, and injectable. Long acting opioids through formulation became available in the late 1980s and 1990s. Now tramadol, oxycodone, codeine, hydromorphone, morphine long acting oral medications along with transdermal fentanyl and buprenorphine are available [29] (**Table 2**).

Several animal and clinical studies have shown codeine, oxycodone, morphine, and fentanyl may have benefit relieving pain for short term but when used long term lead to glial and immune cells activation, leading to tolerance, allodynia, and hyperalgesia [30, 31]. Hydromorphone long-term use has similar effect, opioid neurotoxicity with twitching, myoclonus, unrestful night sleep, and minor agitation. Activation of glial cell is associated with N-methyl-D-Aspartate (NMDA) receptor and release of amino acid, glutamate which is neuroexcitatory [30, 31]. None of the above opioids have NMDA antagonism. Methadone and levorphanol have two racemic mixtures opioid with half-life 7–8 h and non-opioid, NMDA antagonist, norepinephrine, and serotonin re-uptake inhibition. Ketamine has NMDA antagonism but adverse effects in relation to tolerance and mental health issues are high [32] (**Table 3**).

#### *3.6.2 Opioid use*

For the use of opioids as analgesics we need to consider pharmacokinetics, active metabolites, half-life, and excretion. "Start low and go slow" has been the principle and in pain crisis either opioid toxicity or pain is not responding requires higher

**11**

**Table 4.**

*suffering.*

*What Do We Need to Consider for Pain Management? DOI: http://dx.doi.org/10.5772/intechopen.93640*

switch is possible [34, 35].

*reduce pain and suffering.*

**Figure 5.**

doses. Opioid switch in such states and 20–30% reduction of equianalgesic opioid need to be considered. Breakthrough pain, if it occurs 10% of 24-h dose of the

The short-term use of opioids may be useful for acute pain, but the long-term use is associated with activation of glial and immune cells with neuroexcitatory

Methadone is available as two racemic mixtures; R-methadone is an opioid with lower half-life and S-methadone is NMDA antagonist, Norepinephrine, and serotonin re-uptake inhibitor. Methadone has been used as harm-reduction for opioid use disorder and being used as an analgesic. Rapid titration using German, Morley Makin, Kansas, and Edmonton method in the form of stepped approach to opioid

*Animal and clinical studies have shown Codeine, Oxycodone, Morphine, and Fentanyl when used long term, leads to neurotoxicity: Tolerance, allodynia and hyperalgesia and we need to consider better interventions to* 

Methadone is also used when neuropathic and nociplastic pain is associated with existing opioid toxicity; twitches, jerks (myoclonus) and neurotoxicity with confusion and delirium. In such state, it is possible to use low dose twice or three times a day and ultra-low dose with slow titration is possible along with existing opioid or co-analgesics can be reduced and stopped gradually if benefit is noted [36]. Patients with mental health issues require higher dose and patients who are comfortable psychologically, pain relief and physical suffering require very low dose of metha-

Nausea, minor hallucinations, and somnolence are common at the start of opioids, if the dose remains the same in a few days often such symptoms fade or require lower

*Neuroexcitatory chemicals enhance pain and the present and future research has a value to improve pain and* 

done for cancer, acute or chronic kidney disease (**Tables 4**–**6**).

dose of opioid or therapeutic intervention for the symptom.

**Glia and Immune cells release neuroexcitatory, pain enhancing substances**

*3.6.3 Adverse effects associated with the use of opioids*

Arachidonic acid and prostaglandins Excitatory amino acids (glutamate) Pro-inflammatory cytokines/chemokines

Reactive oxygen and nitrogen species

Nerve growth factors

opioid is used as a dose and around half-life such dose is given [33].

chemicals along with tolerance and hyperalgesia [30, 31] (**Figure 5**).

doses. Opioid switch in such states and 20–30% reduction of equianalgesic opioid need to be considered. Breakthrough pain, if it occurs 10% of 24-h dose of the opioid is used as a dose and around half-life such dose is given [33].

The short-term use of opioids may be useful for acute pain, but the long-term use is associated with activation of glial and immune cells with neuroexcitatory chemicals along with tolerance and hyperalgesia [30, 31] (**Figure 5**).

#### **Figure 5.**

*Pain Management - Practices, Novel Therapies and Bioactives*

**Boundary setting—high risk—opioids** Strict boundary setting is essential Treatment agreements—(verbal/signed)

**What activates glia and immune cells?**

Pro-inflammatory cytokines

Endogenous danger signals

*considering how to approach pain management.*

Urine drug testing (UDT) Interval/contingency dispensing

**Table 2.**

**Table 3.**

*improving behaviour.*

Chemokines ATP

Neuropeptides Prostaglandins Glutamate Nitric oxide

Opioids use has been common, and morphine was considered as a "gold standard" for pain management few decades ago along with "no ceiling". Initially, morphine was used for acute pain when the pain was excessive and Twycross, once he was able to establish physiological half-life of morphine, suggested every 4 h, and on the clock. In the early 1980s and before, opioids were short-acting oral pills, liquid, and injectable. Long acting opioids through formulation became available in the late 1980s and 1990s. Now tramadol, oxycodone, codeine, hydromorphone, morphine long acting oral medications along with transdermal fentanyl and

*Long-term opioid use can activate glia and immune cells causing tolerance, allodynia, and hyperalgesia and* 

*High risk in a patient with opioids or substance and opioid use disorder likely, consider boundary setting and* 

Several animal and clinical studies have shown codeine, oxycodone, morphine, and fentanyl may have benefit relieving pain for short term but when used long term lead to glial and immune cells activation, leading to tolerance, allodynia, and hyperalgesia [30, 31]. Hydromorphone long-term use has similar effect, opioid neurotoxicity with twitching, myoclonus, unrestful night sleep, and minor agitation. Activation of glial cell is associated with N-methyl-D-Aspartate (NMDA) receptor and release of amino acid, glutamate which is neuroexcitatory [30, 31]. None of the above opioids have NMDA antagonism. Methadone and levorphanol have two racemic mixtures opioid with half-life 7–8 h and non-opioid, NMDA antagonist, norepinephrine, and serotonin re-uptake inhibition. Ketamine has NMDA antagonism but adverse effects

For the use of opioids as analgesics we need to consider pharmacokinetics, active metabolites, half-life, and excretion. "Start low and go slow" has been the principle and in pain crisis either opioid toxicity or pain is not responding requires higher

in relation to tolerance and mental health issues are high [32] (**Table 3**).

buprenorphine are available [29] (**Table 2**).

**10**

*3.6.2 Opioid use*

*Animal and clinical studies have shown Codeine, Oxycodone, Morphine, and Fentanyl when used long term, leads to neurotoxicity: Tolerance, allodynia and hyperalgesia and we need to consider better interventions to reduce pain and suffering.*

Methadone is available as two racemic mixtures; R-methadone is an opioid with lower half-life and S-methadone is NMDA antagonist, Norepinephrine, and serotonin re-uptake inhibitor. Methadone has been used as harm-reduction for opioid use disorder and being used as an analgesic. Rapid titration using German, Morley Makin, Kansas, and Edmonton method in the form of stepped approach to opioid switch is possible [34, 35].

Methadone is also used when neuropathic and nociplastic pain is associated with existing opioid toxicity; twitches, jerks (myoclonus) and neurotoxicity with confusion and delirium. In such state, it is possible to use low dose twice or three times a day and ultra-low dose with slow titration is possible along with existing opioid or co-analgesics can be reduced and stopped gradually if benefit is noted [36]. Patients with mental health issues require higher dose and patients who are comfortable psychologically, pain relief and physical suffering require very low dose of methadone for cancer, acute or chronic kidney disease (**Tables 4**–**6**).

#### *3.6.3 Adverse effects associated with the use of opioids*

Nausea, minor hallucinations, and somnolence are common at the start of opioids, if the dose remains the same in a few days often such symptoms fade or require lower dose of opioid or therapeutic intervention for the symptom.


#### **Table 4.**

*Neuroexcitatory chemicals enhance pain and the present and future research has a value to improve pain and suffering.*


*Opioid use as an analgesic, "start low and go slow" for pain management. Once pain is stable, same long acting opioid can be used to reduce tolerance. Medications Fentanyl patch, Methadone and Buprenorphine patch are long acting, and dose need to be adjusted, taking half-life into consideration.*

#### **Table 5.**

*Opioid use as an analgesic and "start low and go slow" for pain management.*


*At the Tom Baker Cancer Centre, Pain Clinic in Calgary, Canada an Internal Protocol was applied to patients with opioids and pain has not improved. Evidence relating to neurotoxicity, tolerance, allodynia, and hyperalgesia methadone has been used at ultra-low dose and slow titration to relieve pain.*

#### **Table 6.**

*Opioid use as an analgesic and "start low and go slow" for pain management.*

Dry mouth and constipation are common and require water sipping and laxatives, respectively.

Respiratory depression can occur with high doses of opioids.

Reduction androgen/testosterone can occur due to long-term use of opioids.

Neurotoxicity can occur associated with infection, renal insufficiency, and other medications; consists of hallucinations, delirium, twitching, jerks (myoclonus) and seizures. Such symptoms require reducing existing opioid, opioid switch, or adjunct medications.

Methadone and other substrates with enzyme interactions can lead to serotonin syndrome and QT/QTc prolongation.

**13**

*What Do We Need to Consider for Pain Management? DOI: http://dx.doi.org/10.5772/intechopen.93640*

**4. Opioids, pain and substance use disorder**

**5. Potential future treatments for pain**

and assist as best as we can.

with research investigation.

nutrition is worthwhile.

management can be better.

function in an individual.

**6. Conclusion**

suboxone.

Carcinomatosis can occur with cancer, intra-abdominal organs and results in bowel obstruction with pain and cramps. If it is localized surgery is helpful. If the obstruction can be seen by gastrointestinal endoscopy a stent can be inserted with pain and obstruction relief. However, if the obstruction on the bowel being multiple sites dexamethasone and somatostatin analogue is used subcutaneously. Initially injectable opioids are used for pain relief, and if obstruction is relived can reduce

Chronic pain in patients with cancer, noncancer injury related, organ failure renal insufficiency, and trauma related individuals if they are at the end of life pain and have substance use disorder (SUD), we need to consider "comfort care" as goals

However, similar patients engaged in survivorship, SUD need to be assessed and mental health/addiction services, need to be collaborated. Some of the patients with SUD or opioid use disorder (OUD) require Mu-agonist therapy using methadone or

We need to consider further research to improve care for individual patient. Chronic pain is considered as an illness with suffering. Several organizations have been working and care providers need to engage in raising questions and proceeding

Investigations and research in relation to genetics, non-opioids like; ion channels, alpha-2-agonists, glia, and immune cells along with non-pharmacological approach physical, psychological, social, spiritual rehabilitation and research in

Palliative care consists of patients with illness in the early phase and advanced end of life care. Patient's wishes, worries, goals of care, and shared decisions along

Chronic pain is an illness and remains as a subjective symptom for an individual.

Acute pain often heals within days to weeks, but when the pain persists from an injury for more than three months chronic pain is considered. Central excitatory chemicals in the central nervous system can increase pain expression. Such change

Interventions like interventional, psychological, physical, pharmacological and nutrition have a value to reduce the chronic pain illness, suffering and improve

Biopsychosocial, spiritual, and medical approach can benefit patient, family, and community. As care providers we ought to be up to date, evidence supported approach to relieve suffering of patient and family. Animal experiments and human clinical research have given care providers knowledge, and application of pain

with subjective symptom like pain need to be considered.

allows anxiety, frustration, and mental health issues.

and stop opioids but somatostatin analogue may continue [43, 44].

*3.6.5 Malignant bowel obstruction (MBO)*

#### *3.6.4 Use of assessment tools*


#### *3.6.5 Malignant bowel obstruction (MBO)*

*Pain Management - Practices, Novel Therapies and Bioactives*

*acting, and dose need to be adjusted, taking half-life into consideration.*

**Cancer clinic internal protocol methadone—Calgary**

*Opioid use as an analgesic and "start low and go slow" for pain management.*

*methadone has been used at ultra-low dose and slow titration to relieve pain.*

*Opioid use as an analgesic and "start low and go slow" for pain management.*

Opioid Half-Life Active metabolites Excretion Start dose Codeine 3–4 hrs Morphine Renal 30 mg Q4h Oxycodone 2–6 hrs Oxymorphone Renal 5 mg Q4h Morphine 2–4 hrs M6G, M3G Renal 1 mg Q4h Hydromorphone 2–4 hrs H6G, H3G Renal 1 mg Q4h Fentanyl patch 17 hrs Norfentanyl Renal 12 mcg/h Methadone 6–150 hrs None known Hepatic 1 mg? Q8h Buprenorphine patch 37 hrs B3G, NorB3G Hepatic 5 mcg/h, Q7days *Opioid use as an analgesic, "start low and go slow" for pain management. Once pain is stable, same long acting opioid can be used to reduce tolerance. Medications Fentanyl patch, Methadone and Buprenorphine patch are long* 

**Opioid pharmacokinetics and use as an analgesic**

Dry mouth and constipation are common and require water sipping and laxa-

**1–7 days 7–14 days 14–21 days 21–28 days 28–35 days 35–42 days** 1 mg daily 1 mg Q12h 1 mg Q8h 2 mg Q8h 3 mg q8h 5 mg Q8h 2.5 mg daily 2.5 mg Q12h 2.5 mg Q8h 5 mg Q8h 7.5 mg Q8h 10 mg Q8h *At the Tom Baker Cancer Centre, Pain Clinic in Calgary, Canada an Internal Protocol was applied to patients with opioids and pain has not improved. Evidence relating to neurotoxicity, tolerance, allodynia, and hyperalgesia* 

Reduction androgen/testosterone can occur due to long-term use of opioids. Neurotoxicity can occur associated with infection, renal insufficiency, and other medications; consists of hallucinations, delirium, twitching, jerks (myoclonus) and seizures. Such symptoms require reducing existing opioid, opioid switch, or adjunct

Methadone and other substrates with enzyme interactions can lead to serotonin

Respiratory depression can occur with high doses of opioids.

• Edmonton symptom assessment system revised (ESAS-R) [40].

**12**

tives, respectively.

**Table 5.**

**Table 6.**

medications.

syndrome and QT/QTc prolongation.

• Brief pain inventory (BPI) [37].

• The DN4 questionnaire [38, 39].

• Opioid risk tool (ORT) [18].

• Roland Morris scale [42].

• Pain disability index (PDI) [41].

*3.6.4 Use of assessment tools*

Carcinomatosis can occur with cancer, intra-abdominal organs and results in bowel obstruction with pain and cramps. If it is localized surgery is helpful. If the obstruction can be seen by gastrointestinal endoscopy a stent can be inserted with pain and obstruction relief. However, if the obstruction on the bowel being multiple sites dexamethasone and somatostatin analogue is used subcutaneously. Initially injectable opioids are used for pain relief, and if obstruction is relived can reduce and stop opioids but somatostatin analogue may continue [43, 44].
