Case report: The lesson from opioid withdrawal symptoms mimicking paraganglioma recurrence during opioid deprescribing in cancer pain

Abstract

Pain is one of the predominant and troublesome symptoms that burden cancer patients during their whole disease trajectory: adequate pain management is a fundamental component of cancer care. Opioid are the cornerstone of cancer pain relief therapy and their skillful management must be owned by physicians approaching cancer pain patients. In light of the increased survival of cancer patients due to advances in therapy, deprescription should be considered as a part of the opioid prescribing regime, from therapy initiation, dose titration, and changing or adding drugs, to switching or ceasing. In clinical practice, opioid tapering after pain remission could be challenging due to withdrawal symptoms’ onset. Animal models and observations in patients with opioid addiction suggested that somatic and motivational symptoms accompanying opioid withdrawal are secondary to the activation of stress-related process (mainly cortisol and catecholamines mediated). In this narrative review, we highlight how the lack of validated guidelines and tools for cancer patients can lead to a lower diagnostic awareness of opioid-related disorders, increasing the risk of developing withdrawal symptoms. We also described an experience-based approach to opioid withdrawal, starting from a case-report of a symptomatic patient with a history of metastatic pheochromocytoma-paraganglioma.

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EDITED BY
Michael Benjamin Larkin,
Baylor College of Medicine, United States
REVIEWED BY
Arjun Singh,
Memorial Sloan Kettering Cancer Center,
United States
Tu Nguyen,
New York University, United States
*CORRESPONDENCE
Elena Ruggiero
elena.ruggiero@iov.veneto.it
RECEIVED 18 July 2023
ACCEPTED 11 September 2023
PUBLISHED 22 September 2023
CITATION
Ruggiero E, Pambuku A, Caccese M,
Lombardi G, Gallio I, Brunello A, Ceccato F and
Formaglio F (2023) Case report: The lesson
from opioid withdrawal symptoms mimicking
paraganglioma recurrence during opioid
deprescribing in cancer pain.
Front. Pain Res. 4:1256809.
doi: 10.3389/fpain.2023.1256809
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© 2023 Ruggiero, Pambuku, Caccese,
Lombardi, Gallio, Brunello, Ceccato and
Formaglio. This is an open-access article
distributed under the terms of the Creative
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distribution or reproduction in other forums is
permitted, provided the original author(s) and
the copyright owner(s) are credited and that the
original publication in this journal is cited, in
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No use, distribution or reproduction is
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terms.
Case report: The lesson from
opioid withdrawal symptoms
mimicking paraganglioma
recurrence during opioid
deprescribing in cancer pain
Elena Ruggiero1*, Ardi Pambuku1, Mario Caccese2,
Giuseppe Lombardi2, Ivan Gallio1, Antonella Brunello2,
Filippo Ceccato3,4 and Fabio Formaglio1
1
Pain Therapy and Palliative Care with Hospice Unit, Veneto Institute of Oncology IOV—IRCCS, Padua,
Italy,
2
Department of Oncology, Oncology Unit 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy,
3
Department of Medicine DIMED, University of Padova, Padova, Italy,
4
Endocrine Disease Unit,
University-Hospital of Padova, Padova, Italy
Pain is one of the predominant and troublesome symptoms that burden cancer
patients during their whole disease trajectory: adequate pain management is a
fundamental component of cancer care. Opioid are the cornerstone of cancer
pain relief therapy and their skillful management must be owned by physicians
approaching cancer pain patients. In light of the increased survival of cancer
patients due to advances in therapy, deprescription should be considered as a
part of the opioid prescribing regime, from therapy initiation, dose titration, and
changing or adding drugs, to switching or ceasing. In clinical practice, opioid
tapering after pain remission could be challenging due to withdrawal symptoms’
onset. Animal models and observations in patients with opioid addiction
suggested that somatic and motivational symptoms accompanying opioid
withdrawal are secondary to the activation of stress-related process (mainly
cortisol and catecholamines mediated). In this narrative review, we highlight how
the lack of validated guidelines and tools for cancer patients can lead to a lower
diagnostic awareness of opioid-related disorders, increasing the risk of
developing withdrawal symptoms. We also described an experience-based
approach to opioid withdrawal, starting from a case-report of a symptomatic
patient with a history of metastatic pheochromocytoma-paraganglioma.
KEYWORDS
cancer pain, opioid, opioid withdrawal, cortisol, catecholamines, opioid deprescribing
1. Introduction
The International Association for the Study of Pain defines pain as “an unpleasant
sensory and emotional experience associated with actual or potential tissue damage or
described in terms of such damage”(1). However, pain is a personal experience,
influenced by psychological and social factors, requiring a personalized and individual
approach that often goes beyond guidelines and definitions.
Most of patients with cancer experience pain as the predominant symptom during their
illness and cancer treatment, thus affecting the quality of life (QoL). More than half of
patients report the presence of moderate-severe pain since cancer diagnosis: its prevalence
increases up to 80% in the advanced stage of the disease (2,3). Cancer pain represents
TYPE Case Report
PUBLISHED 22 September 2023
|
DOI 10.3389/fpain.2023.1256809
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one of the main determinants of QoL and performance status,
causing significant limitation in the activities of daily living.
Adequate pain management, with pharmacological and non-
pharmacological strategies, is therefore essential to preserve QoL
and optimize tolerance to life-prolonging treatments, without the
need for dose reduction (2–4).
The correct assessment and quantification of pain are essential
in the management of cancer patients. Cancer pain treatment is
based on the expert use of non-steroidal anti-inflammatory drugs
(NSAIDs), opioid, and adjuvant drugs. NSAIDs are indicated for
mild to moderate pain, and their side effects are common and
relevant in clinical practice. The use of opioid drugs is indicated
in the treatment of patients with moderate to severe pain. At
each step, the use of adjuvant drugs should be considered (5–7).
When opioid drugs have to be prescribed, it must always be
taken into consideration the pharmacokinetic and
pharmacodynamic bases of tolerance and dependence
development. Furthermore, the onset of side effects should be
prevented: the patient must always be informed immediately.
As World Health Organization (WHO) suggests, a tiered and
personalized approach is needed. The use of non-
pharmacological pain management techniques is of utmost
importance, to optimize the clinical response. The psychologist
should be involved as an active part of the treatment, concurrent
with the start of pharmacological therapy. Patients on opioid
therapy should be adequately screened for the risk of developing
Opioid Use Disorders (OUD). It is of utmost importance to
differentiate physical dependence from addiction because
psychological vulnerability is relevant in patient with cancer. The
onset of withdrawal symptoms after a rapid reduction in opioid
dosage, or because of the administration of an antagonist, defines
physical dependence. As a precaution, patients should always be
considered physically dependent after regular treatment with an
opioid drug. Contrariwise, addiction is a syndrome characterized
by the loss of control over the use of drugs and by compulsive
and continuous use. This is not a pharmacological property of
opioid and must be distinguished from physical dependence (5–7).
Although the literature shows a clear increase in the survival of
cancer patients, there are still very few studies that have
investigated the risk of OUD and withdrawal syndrome in
patients with cancer, in which it is possible to plan a tapering or
even a cessation of the relief-pain therapy. While there are many
studies and clear guidelines on the choice and management of
pain therapy in patients with cancer, to date there are no defined
guidelines on the tapering of therapy in these patients and on
the management of withdrawal symptoms in patients who do not
develop addiction.
The clinical case presented allowed us to reflect on the thin red
line between the symptoms that may indicate a disease recurrence
and those related to opioid tapering, focusing our attention on the
need for adequate tools to monitor patients during the
deprescribing process. Therefore, the purposes of the article are
to highlight the clinical skills and challenges related to opioid
therapy in cancer pain, and to suggest how the lack of validated
tools for the cancer patient represents a limitation in the process
of prescription and deprescription.
2. Case presentation: opioid
withdrawal mimics a symptomatic
recurrence in a patient with metastatic
pheochromocytoma-paraganglioma
In April 2010, a 38-year-old female underwent left trans-
parotid cervicotomy after the discovery of a left parapharyngeal
neoformation. Histology confirmed the diagnosis of vagal
paraganglioma. Oncological staging with total body computed
tomography (CT) scan and 18F-FDG positron emission
tomography did not show distant metastases, urinary
catecholamine levels were normal. Therefore, the patient started a
clinical and radiological follow-up. Pheochromocytomas and
paragangliomas are rare endocrine neoplasms, composed of
chromaffin cells, characterized by particular clinical
manifestations (due to often catecholamines secretion), and often
with a benign outcome after surgery. They are grouped together
in the same pheochromocytoma and paraganglioma syndrome
(PPGL) (8).
In February 2019 she reported back pain (Numeric Pain Rating
Scale, NPRS 8/10), therefore she underwent a total spine CT scan
with evidence of an osteolytic lesion of the posterior portion of
D10 (depicted in Figure 1) that extended, without involvement,
to the spinal cord. A biopsy of the D10 osteolytic lesion was
performed and confirmed paraganglioma vertebral metastasis.
In April 2019 the patient underwent decompressive surgery, en
bloc resection of D10, and stabilization of the spine. After this
procedure, the patient continued radiological and orthopedic
follow-up without finding new-onset metastases. A genetic
testing (with next-generation sequencing detection technology)
excluded pathogenic mutations. The back pain due to osteolytic
lesion was unresponsive to NSAIDs, therefore she started
oxycodone 10 mg BID and gabapentin 300 mg BID from May
2019 (the timeline of the treatment is depicted in Figure 1).
The oxycodone dosage was progressively increased according
to the patient’s reported NPRS, until the highest dose of 30 mg
TID plus rescue therapy with oxycodone/paracetamol 20 mg/
325 mg, with benefit on the symptom.
In September 2019 she complained dyspnea: a CT scan
revealed right pleural effusion. Histology confirmed the presence
of mesothelial hyperplasia and inflammatory infiltration in the
absence of neoplastic cells, after a right zonal pleurectomy. A
vertebroplasty of D9 and D8 in January 2020 and subsequent L4-
L5 arthrodesis in July 2020 were performed to reduce the
instability of the dorsal spine. Finally, in November 2021 she
underwent an expansion of the back-lumbar stabilization to L4
for the persistence of pain and a sensation of sagging of the
lumbar spine, with a reduction on the reported symptom. Opioid
treatment was not changed before and after surgical procedures.
She started a progressive monthly tapering of the oxycodone
dosage from August 2022, reducing the dosage by about 10%–
15% at each step, until reaching the minimum dosage of 10 mg
TID in December 2022 with the aim of continuing the
progressive reduction of the dosage based on the referred pain
(titration and tapering of oxycodone is detailed in
Supplementary Table S1). The gabapentin dosage was maintained.
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Although there had been no resurgence of pain, suddenly, after
about 7–10 days from the reduction from 15 + 15 + 10 mg per day
to 10 mg TID, she developed episodes of incoming hypertensive
crises: average arterial pressure was 150/80 mmHg, with
hypertensive peaks up to 200/100 mmHg especially at night. She
also reported palpitations and profuse sweating.
Furthermore, at outpatient clinical evaluation, the patient
presented with anxiety, increased respiratory rate, stomach
cramps, tachycardia until 100–110 beats per minute, anorexia,
and nausea. The symptoms described could- be associated with a
secreting recurrence of the paraganglioma (despite normal
urinary fractionated catecholamines and metanephrines levels,
measured with high-performance liquid chromatography and UV
detector: normetanephrine 0.16 μmol/24 h, range 0.01–2.13;
metanephrine 0.1 μmol/24 h, range 0.01–1.62; adrenaline
17 nmol/24 h, range 5–110; noradrenaline 141 nmol/24 h, range
40–600). Therefore, therapy with doxazosin 2 mg TID was
started, and oxycodone therapy was re-boosted at 15 + 15 + 10 mg.
After the increase of the oxycodone dosage and the
introduction of doxazosin, the symptoms rapidly disappeared,
with a return to normal blood pressure values after a week
(average arterial pressure 120/70 mmHg), without palpitations
and sweating, allowing the suspension of the antihypertensive
therapy already after about 15 days.
CT scan and 18F-FDG positron emission tomography were
performed and excluded a paraganglioma recurrence. The
radiological features, combined with clinical data and endocrine
evaluation, allowed us to conclude that the symptomatology
reported by the patient could be attributed to opioid withdrawal
which mimicked a recurrence of secreting paraganglioma.
The rapid disappearance of symptoms with the resumption of
oxycodone therapy, the tests performed and the overall clinical
picture of the patient led us to exclude other possible causes of
hypertension, palpitations and sweating, such as peri-menopausal
hormonal variations. After the excluding of recurrent disease, it
was agreed with the patient to maintain the dosage of oxycodone
until now. A new tapering effort will be planned using a
premedication with α
2
agonists (Clonidine).
3. Pain management in cancer: the role
of opioid
Opioid are the cornerstone of cancer pain relief therapy.
Opioid therapy should be administered at different stages of the
disease, according to the clinical presentation (9). In choosing
the most appropriate therapy, the characteristics of each opioid
should be tailored to the clinical features of the individual
patient. Pharmacokinetics, pharmacodynamics, adverse events,
toxicity, and drug interactions should be considered before
treatment. As regards the patients, we must consider gender, age,
the possible presence of genetically correlated alterations, site of
the primary tumor and metastases, pain characteristics (duration,
onset, irradiation, and so on), and any allergies and intolerances,
co-morbidities, simultaneous oncological and non-oncological
treatments, and excretory organ function (10).
As suggested by the guidelines of the different scientific
societies (European Association for Palliative Care, American
Society of Clinical Oncology, European Society for Medical
Oncology, and WHO) and their most recent revisions, pain-relief
therapy and opioid prescribing is based on the WHO steps scale,
since 1986 (11–16). In particular:
•weak opioids, such as codeine and tramadol, are recommended
if pain is reported as mild to moderate, there are no substantial
differences in the choice of drug to start with.
•strong opioids (i.e., morphine, and oxycodone) are
recommended when the pain intensity is moderate to severe.
For many years, morphine was considered the first-choice opioid
for the treatment of moderate to severe cancer pain. The
availability of new molecules and different routes of
administration has raised the question of opioid choice. In 2007,
FIGURE 1
Timeline depicting the clinical history of the patient (in purple) and pain management (in green). On the right: osteolytic lesion of the posterior portion of
thoracic vertebra (D10). Panel (A–C) Axial plane; panel (D) sagittal plane.
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a Cochrane Review (17) investigated the role of oral morphine for
cancer pain treatment, including 3,749 patients in 54 studies. The
high heterogeneity of study design (thirteen and six studies
compared modified-release or immediate-release morphine with
other opioid respectively, and the others compared different
morphine formulations) and the low number of patients
recruited in each trial (fewer than 100 participants) were not able
to detect a superiority between the formulations or comparative
drugs. An updated Cochrane Review confirmed these results:
similar efficacy on analgesia and side-effects in opioid-naive
patients were reported for oral morphine, oxycodone, and
hydromorphone. In clinical practice, several opioid drugs are
regularly prescribed in patients with cancer pain: oral morphine
(18), oxycodone, or fentanyl (19–23). Only a few differences have
been identified across the opioid investigated for the treatment of
cancer-related pain, and none of the investigated agents offered a
safer profile in terms of adverse events (24).
The choice of the most appropriate opioid for the treatment of
moderate or severe cancer pain should balance pharmacokinetic
properties (first bioavailability) and the route of administration.
Furthermore, in cases of organ failure or renal/kidney
impairment, clinicians should try to avoid complications and
toxicities. Unless there are no alternatives, morphine should be
avoided in case of moderate to severe renal impairment.
Oxycodone, fentanyl, and hydromorphone should be carefully
monitored because they are primarily excreted in urine (17). A
systematic review in 2022 evaluated the use of opioid in patients
with cancer and hepatic impairment. The results, conducted in
less than a hundred patients, were not sufficient to indicate a
preferred opioid in cancer patients with liver dysfunction (25).
According to guidelines, opioid therapy should be initiated as
immediate-release formulations and used first on demand for
symptom control, at the lowest dose to achieve acceptable analgesia,
that can be shared with the patient’sexpectations(12,24). After
adequate titration, extended-release or long-acting opioid
formulation should be provided with around-the-clock dosing in all
patients, with the supply of a rescue short-acting medication to
manage breakthrough or transient pain exacerbations (12,26,27).
For better pain relief, patients who have been taking other
analgesics, such as NSAIDs, may continue these analgesics for a
limited time after opioid initiation, if these agents provide
additional analgesia and are not contraindicated (24). In
addition, for neuropathic pain in advanced cancer patients with
opioid failure, the combination with an adjuvant effective in
neuropathic cancer pain (GABA-inhibitors, duloxetine, tricyclic
antidepressants) has to be considered (5).
3.1. Opioid side effects
The most common side effects of long-term opioid
administration are constipation, nausea and vomiting, sedation
and dizziness, physical tolerance and/or dependence, and
respiratory depression. Less common adverse events are delayed
gastric emptying, immunologic and hormonal dysfunction
(especially regarding cortisol secretion), muscle rigidity and
myoclonus, and opioid-induced hyperalgesia. Among them,
opioid-induced constipation and nausea are challenging
symptoms: they often persist because tolerance does not develop,
especially the former. Opioid-induced side effects may be severe
enough to require a dose reduction or drug discontinuation (28).
Tolerance, a loss of analgesic efficacy, could lead to progressive
increasing dose requirements. Tolerance can be divided into two
main classifications:
•Innate: the predisposition genetically determined, that starts
from the first opioid dose;
•Acquired: the consequence of repeated drug exposure and
linked to pharmacokinetics and pharmacodynamics (29).
Moreover, physical dependence and addiction could prevent
proper prescribing and inadequate pain management (28).
Pain relief therapy could be insufficient to control symptoms
in some opioid-seeking patients; therefore, the term pseudo-
addiction has been used to indicate when the clinical
presentation is secondary to pain under-treatment of pain,
rather than addiction (30).
3.1.1. Opioid-induced constipation (OIC)
The prevalence of OIC ranges from 40% to 95% of opioid-
treated patients: its consequences increase morbidity and
mortality, with a significant QoL reduction. Finally, long-term
chronic constipation can also result in rectal pain, burning,
hemorrhoid formation until bowel obstruction with potential
bowel rupture, and death (31).
Three subtypes of opioid receptors are reported: μ,δ,orκ.
Analgesia is mainly achieved through stimulation of central μ
receptors; however, opioid receptors are the natural ligands for
endogenously produced neurotransmitters in the central and
peripheral nervous systems. Opioid activates also those μ
receptors in the gastrointestinal tract that control gut motility
(32,33). Their activation results in opioid-induced adverse
gastrointestinal effects: increased sphincter tone, reduced
secretions and increased water absorption, reduced gastric emptying,
and reduced propulsion of chime through the intestine (34).
Prevention and treatment of constipation are essential for
the management of opioid treatment: the combination with
prophylactic laxatives is recommended early, also before the
opioid prescription. The two most used central opioid receptor
antagonists are naloxone and naltrexone. The former acts also
in the peripheral nervous system, it can be administered
separately from opioid medications, or combined in fixed-dose
tablets. A significant first-pass metabolism explains the
predominant intestinal effect of naloxone, explaining its role
in treating OIC (35). On the contrary, the Peripherally Acting
μOpioid Receptor Antagonists (PAMORAs) are developed to
selectively block peripherally located μopioid receptors,
with minimal effects on the centrally mediated analgesic
properties (36).
3.1.2. Opioid-induced nausea and vomiting (OINV)
The activation of opioid receptor in central and peripheral sites
leads to OINV (37). The OINV impact on treatment adherence
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often leads to inadequate pain management; a persistent long-term
OINV negatively impacts patient’s functional outcomes, well-
being, and mental health (38). Several individual factors, such as
age, sex, race, genetic polymorphisms, and metabolic differences
in pharmacodynamics/pharmacokinetics can explain the large
inter-individual variability of OINV onset (39). The incidence of
nausea and vomiting after opioid treatment is lower in geriatric
patients, while females may have a 60% higher risk of OINV (39,
40).
3.1.3. Opioid-induced hyperalgesia (OIH)
In the long-term management of opioid analgesic therapy,
opioid-induced hyperalgesia (OIH) is a paradoxical opioid effect
and should not be forgotten: OIH often leads to the need to
reduce or modify the therapy (41). OIH is defined as a state of
nociceptive sensitization caused by opioid exposure. It is a
paradoxical, excessive, and disproportionate pain response in a
patient receiving opioid pain therapy, and therefore non-painful
stimuli could be perceived negatively by the patient (42).
Treating OIH is often a time-consuming clinical challenge.
The main available options include opioid treatment
discontinuation or switch to a different opioid, or a low-dose
start due to incomplete cross-tolerance, allowing an overall
dose reduction. Improved analgesia after opioid rotation has
been reported in several clinical situations (43). The use of
NMDA antagonists, able to prevent opioid tolerance, is used
to manage OIH (44); but there are no large randomized
controlled trials and data are not robust. An approach that
combines different drugs, as pregabalin and COX-2 inhibitors,
may play a role in OIH management (45).
4. Opioid use disorders (OUD)
Substance use disorders are chronic illnesses characterized by
relapse and remission: OUD definition includes tolerance and
withdrawal (46). A checklist of symptoms developed by the
American Psychiatric Association is defined in the Diagnostic
and Statistical Manual of Mental Disorders, 5th Edition (DSM-5)
is used to diagnose OUD (47). It represents an epidemiological
emergency, associated with increased mortality, sharply
increasing in recent years: an estimated 10.3 million people in
the United States misused opioid in 2018, including 9.9 million
people who misused opioid for pain treatment (47). Vulnerability
to OUD can be affected by several innate and acquired factors,
such as genetic background, prolonged exposure to μ-opioid
agonists for analgesia, untreated underlying psychiatric disorders,
young-er age, and social/familial background (48).
OUD assessments proposed by The American Society of
Addiction Medicine are structured around six dimensions: acute
intoxication, medical conditions and complications, emotional
and cognitive conditions or complications, readiness for change,
continued use or continued problem potential, recovery/living
environment.
4.1. Glossary
4.1.1. Abstinence
The intentional and consistent restraint from the pathological
pursuit of reward and/or relief. Abstinence involves the use of
substances and other behaviors. The term abuse is not
recommended for clinical or research purposes, it was previously
applied to psychoactive substance-related disorders in the DSM.
4.1.2. Addiction
It is the inability to stop a substance. It is defined as a chronic,
relapsing disorder, characterized by compulsive drug seeking and
use despite adverse harmful consequences. Addiction is a chronic
medical condition that combine the interactions among brain
circuits, genetic background, environment, and an individual’s
life experiences.
4.1.3. Dependence
Physical dependence is a “state of neurological adaptation that
is manifested by a drug class-specific withdrawal syn-drome,
produced by abrupt cessation, rapid dose reduction, decreasing
blood level of the drug, and/or administration of an antagonist”
- psychological dependence is a “subjective sense of need for a
specific psychoactive substance, either for its positive effects or to
avoid negative effects associated with its abstinence”.
4.1.4. Tolerance
The reduced responsiveness to an opioid agonist that occurs with
its long-term use. Accelerated metabolism and excretion are defined
as metabolic tolerance. On the contrary, the central nervous system is
less sensitive to the agonist in functional tolerance.
Opioid withdrawal begins when the agonistic activity of opioid
receptor is reduced after the metabolism of the last dose, after drug
discontinuation or antagonist therapy. Withdrawal syndrome is
characterized by somatic and psychological symptoms.
[reassumed in Figure 2].
5. Opioid withdrawal in clinical
practice
According to the DSM-5 and as defined in the previous section,
withdrawal from a substance is defined as “the substance-specific
problematic behavioral change, with physiologic and cognitive
components, that is due to the cessation of, or reduction in,
heavy and prolonged substance use”and in the International
Classification of Diseases, 10th edition, as “a group of symptoms
of variable clustering and severity occurring on absolute or
relative withdrawal of a psycho-active substance after persistent
use of that substance”(49). In clinical practice, common signs
and symptoms of opioid withdrawal syndrome are hypertension,
tachycardia, nausea, vomiting, diarrhea, mydriasis, piloerection,
lacrimation, rhinorrhea, and insomnia (50,51).
It is generally accepted that a gradual reduction should not be
accompanied by the appearance of withdrawal symptoms, while
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these are to be expected with more robust decreases (52). The drug
half-life is one of the main features that affect the onset (early or
delayed) opioid withdrawal and the duration of the clinical
syndrome. The mechanism of withdrawal, especially regarding
the interactions between opioid and noradrenergic systems,
explains the symptoms (53,54). In clinical practice, some
common symptoms (such as sedation, hypotension, and reduced
respiration rate) are secondary to the suppressed norepinephrine
release induced by the μreceptor opioid cAMP-mediated
activation on noradrenergic neurons in the locus coeruleus (53,
55,56). In chronic opioid use, this pathway regains, leading to a
norepinephrine excess in the locus coeruleus, which underlies the
characteristic symptoms of opioid withdrawal. The μ-opioid
receptor agonists and partial agonists (as methadone and
buprenorphine) and α2 agonists (clonidine and lofexidine) are
used to treat opioid withdrawal symptoms.
5.1. Evaluation scales for withdrawal
syndrome
There are many scales, tools, and questionnaires that could be
useful in the diagnosis and during follow-up of opioid withdrawal
syndrome, such as:
•Objective Opioid Withdrawal Scale (OOWS) (57),
•Clinical Opioid Withdrawal Scale (COWS) (58),
•Slubjective Opioid Withdrawal Scale (SOWS) (59).
None of these tools has been specifically validated for the patient
with cancer pain.
5.2. Feasible pharmacological treatment of
withdrawal syndrome
Evidence-based recommendations are lacking: randomized
controlled trials are not available to establish which drug is the
most suitable for the management of withdrawal symptoms
during opioid reduction or withdrawal, particularly in cancer
patients (50).
Drug choice strongly depends on the expected goal.
Buprenorphine is probably the treatment of choice if the target is
the discontinuation of opioid therapy in patients still
complaining of pain, given its superiority in terms of pain
control over α
2
agonists. However, buprenorphine alone does not
control withdrawal symptoms, and α
2
agonists can be combined
with adjuvant drugs.
Methadone and buprenorphine are both recommended for the
management of opioid withdrawal, their reduction of withdrawal
symptoms and improvement of opioid abstinence are similar.
FIGURE 2
Balance among opioid tolerance and addiction. On the one hand we have the physiological mechanisms of tolerance and physical dependence on
opioid. On the other hand, the alarm bells that every doctor must keep in mind during pain-relieving therapy with opioid. Not paying adequate
attention to the risk factors which, even in the patient with cancer, can lead to addiction, causes the balance between the two aspects of opioid
therapy to become unbalanced. A careful anamnesis and the close monitoring of the patient, allows the physician to keep the two pans of the scales
in balance, obtaining the maximum pain response and minimizing the risks. Created with BioRender.com.
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Methadone is contraindicated in case of acute bronchial asthma or
hypercapnia, and in known or suspected paralytic ileus. Methadone
use should be carefully balanced with adverse events in patients
with psychiatric disorders, decompensated liver disease,
respiratory insufficiency, or concomitant use of sedative,
hypnotic, anxiolytic or other QT-interval affecting drugs.
Attention should be paid to the substances that interfere with
this cytochrome P450 enzyme, such as anticonvulsants,
antiretrovirals, and alcohol (60).
Buprenorphine is a partial µopioid receptor agonist available
in different formulations, most of which have been approved by
the Food and Drug Administration (FDA) since 2015.
Buprenorphine is recommended for the pharmacological
treatment of OUD and opioid withdrawal: results are similar to
methadone, and superior to lofexidine or clonidine (61–64).
Buprenorphine should also be used with caution in patients with
current or previous hepatic dysfunction, and in patients who
have concomitant alcohol or sedative use, hypnotic, or anxiolytic
use disorder. Moreover, buprenorphine use in patients with
hypovolemia or severe cardiovascular disease may emphasize its
hypotensive effects. Significant medication interactions include
alcohol, sedatives and agents that affect CYP3A4 activity (azole
antifungals, macrolide antibiotics such as erythromycin, and HIV
protease inhibitors).
Alpha-2 adrenergic agonists can be used to treat withdrawal
syndrome when patients reduce buprenorphine or methadone.
0.1–0.3 mg of Clonidine every 6–8 h, with a maximum dose of
1.2 mg daily, is used until side effects (mainly arterial
hypotension). Clonidine is often combined with other non-
narcotic medications targeting specific opioid withdrawal
symptoms (as benzodiazepines for anxiety, loperamide for
diarrhea, acetaminophen or NSAIDs for pain) (65).
Buprenorphine, in contrast, is less limited in several countries.
It was introduced for the first time in the U.S. for the treatment of
OUD under the Drug Addiction Treatment Act of 2000 (DATA
2000) (66,67). It allows buprenorphine prescription in
outpatients by any licensed physician after a dedicated training.
In the US, regulatory restrictions on the use of opioid agonists
(or partial agonists) for the treatment of OUD require new
legislation that considers the use of buprenorphine. In 2002, the
FDA approved buprenorphine in patients with OUD (66,67). In
a 2017 Cochrane review (68), Gowing collected the available
clinical evidence regarding the utility of buprenorphine in the
treatment of opioid withdrawal. Authors reviewed 27 studies
involving 3,048 individuals; the collected manuscripts compared
buprenorphine with clonidine or lofexidine (n= 14),
buprenorphine with methadone (n= 6), or buprenorphine
tapering (n= 7). Buprenorphine was associated with a lower
withdrawal score than α
2
agonists (clonidine and lofexidine,
seven studies in 902 patients), longer retention in treatment (five
studies, 558 patients), and increased likelihood of withdrawal
treatment completion (12 studies in 1,264 cases). A direct
comparison among studies was not feasible because each author
used a different scale. In such scenario, an effort of the scientific
community is to homogenize the scale used. Buprenorphine was
similar to methadone in terms of treatment duration or
completion rate. Clonidine reduces noradrenergic hyperactivity in
locus coeruleus neurons that cause opioid withdrawal symptoms,
and therefore is effective in patients (53,56,69). In a 2016
Cochrane review, Gowing and colleagues (65) investigated the
use of α
2
agonists (especially clonidine and in minor parts
lofexidine, tizanidine, and guanfacine) in the treatment of opioid
withdrawal. α
2
agonist treatment (five studies with clonidine, one
with lofexidine) was more effective than placebo and more likely
to result in the completion of treatment, withdrawal signs and
symptoms occurred and resolved earlier than methadone, and
treatment duration was shorter. Also in this case measures of
withdrawal severity differed between studies (50).
6. Endocrine aspects of opioid use and
withdrawal
Several drugs (not only opioid) are able to modulate the activity
of the hypothalamic–pituitary–adrenal (HPA) axis or the
sympathetic nervous system, leading to an impaired secretion or
activity of respectively cortisol or catechol-amines. Moreover,
somatic and motivational symptoms accompanying opioid
withdrawal are secondary to the activation of stress-related
processes (either cortisol or catecholamines).
The impact of chronic opioid administration and its final result
in HPA axis tolerance-induced and abstinence-induced ACTH/
cortisol hypersecretion has been extensively studied in animal
models. In rats, ACTH and corticosterone (rat steroidogenesis
does not secrete cortisol) responses to CRH and ACTH were not
related to morphine tolerance (70). In mice, a systemic
pretreatment with prazosin or propranolol (the selective
antagonists of the α
1
-adrenergic and the β-adrenergic receptor,
respectively), or with spironolactone (the mineralocorticoid
receptor antagonist) decreased somatic symptoms of morphine
withdrawal (induced with naloxone after a chronic morphine
treatment), allowing to measure somatic and affective/
motivational aspects of physical morphine dependence. The
withdrawal symptoms assessed in the study were jumps, rearing,
paw tremors, body tremors, wet-dog shakes, teeth chattering,
defecations, and urinations. Moreover, in the same model, only
propranolol pretreatment attenuated the dysphoric affective state
accompanying opioid withdrawal (71). Lateral hypothalamic
orexin system function extends beyond reward seeking: it can
play a role in the expression of addiction-like state in rats (72).
The locus coeruleus is involved in opioid addiction development:
in mice, hypothalamic hypocretin innervation increases after
morphine administration, correlated with an increase in tyrosine
hydroxylase expression (the enzyme that catalyzes the rate
limiting step in this synthesis of catecholamines). Elimination of
hypocretin neurons prevents the tyrosine hydroxylase increase
and reduces the somatic and affective components of opioid
withdrawal (73). Depleted animals showed a significant decrease
in the global withdrawal syndrome score compared with intact
controls after naloxone-precipitated withdrawal (73). C1 neurons
in the rostral ventrolateral medulla express the adrenaline-
synthesizing enzyme phenylethanolamine N-methyltransferase:
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chronic morphine use in rats produces a selective internalization of
mu-opioid receptors in C1 neurons, and may precipitate the
sympathetic hyperactivity during acute opioid withdrawal (74).
Finally, it has been speculated that some opioid can be quickly
converted to catecholamines in vivo. It is suggested to occur in
addition to the acute conversion into their known metabolites,
and can play a role in abuse and dependence. Not only analgesic
opioid (morphine and oxycodone) but also their antagonists
(naltrexone and naloxone) may be converted to catecholamines
through a series of currently unidentified reactions. From a
chemical point-of-view, the molecule of morphine and
oxycodone contain some domains (especially methyl groups): the
formation of dopamine or epinephrine is possible if these methyl
groups are enzymatically removed (75).
In humans, chronic opioid dependence may cause the altered
function of the HPA axis, and opioid withdrawal may change
cortisol or amine concentrations. In 2008 it has been reported a
decreased pituitary responsiveness and an increased adrenal
cortisol response in two groups of patients with opioid
dependence treated with benzodiazepines and clonidine (30
patients), or with methadone (30 patients). CRH concentration
during acute abstinence was lower in patients treated with
benzodiazepines and clonidine or methadone; CRH levels then
normalized 30 and 90 days after withdrawal in the former group.
Contrariwise, ACTH levels were similar to controls. Cortisol
levels during acute abstinence were higher in patients treated
with benzodiazepines and clonidine and lower in those treated
with methadone (both with respect to controls) (76). Metyrapone
test is considered convenient and sensitive, when compared with
the insulin-induced hypoglycemia, to assess the integrity of HPA
axis function (77). The metyrapone test was performed in 18
methadone-maintained former heroin addict patients, 10 without
and 8 with ongoing cocaine dependence, resulting in ACTH
hyperresponsivity in the latter group (78).
In mammals, not only the adrenal cortex (HPA axis) but also
the adrenal medulla (with catecholamines) is involved in stress
response and may be affected by opioid use and its withdrawal.
Plasmatic adrenaline concentrations in-crease up to 30-fold (with
a minor magnification of noradrenaline) after the initial injection
of naloxone during ultra-rapid opioid detoxification, leading to
increased heart rate and stroke volume (79). In the same setting
of naloxone receptor blockade for opioid detoxification, pre-
administration of the α
2
-adrenoceptor agonist clonidine decreases
the muscle sympathetic activity and catecholamine plasma
concentrations (80). However, a concomitant antisocial
personality disorder (ASPD) can induce a possible impairment of
this clonidine effect (81).
Some case reports support the evidence that opioid
withdrawal leads to sympathetic hyperactivity and increased
catecholamine release, which may trigger catecholamine-induced
cardiomyopathy, resulting in heart failure and fatal arrhythmias
(8). Takotsubo is characterized by transient left ventricular apex
wall motion abnormality, similar to acute coronary syndrome but
with normal coronary artery flow. In 2021, it has been reported a
case of a woman with a past history of intravenous drug abuse
on opioid substitution treatment with buprenorphine. She
presented in the Emergency Department with tachycardia,
tachypnea, and bilateral rales; she reported that she did not use
buprenorphine for three days. A takotsubo cardiomyopathy was
found in left ventriculography (apical ballooning): opioid
withdrawal mediates sympathetic overdrive and may trigger
takotsubo syndrome development (82). The main hypothesis for
the physiopathology of takotsubo is that a rapid and significant
increase of serum catecholamines (secondary to a stressful event:
it was also known as the “broken heart syndrome”may cause
microvascular coronary spasm, with inflammation and
dysfunction (83). The main model of sympathetic
overstimulation is pheochromocytoma and its related
cardiomyopathy (84).
Clonidine is a central α
2
-adrenoreceptors agonist, it reduces
sympathetic outflow and noradrenaline release from sympathetic
nerve endings. Obviously, autonomous catecholamine secretion
from pheochromocytoma-paraganglioma (PPGL) is not affected
by clonidine: suppression test with clonidine is used in patients
with suspected PPGL and moderate endocrine excess (85).
Evidence-based studies regarding endocrine aspects of
withdrawal syndrome are limited in patients that use opioids for
addiction, and extremely limited in cancer patients during the
withdrawal phase. Catecholamine-based symptoms are only a
puzzle piece of the several aspects that must be considered in a
holistic approach when facing a patient.
7. The opioid deprescribing in cancer
pain
In the last decades, cancer-therapy improvements have
dramatically changed the natural history of the disease for many
patients, modifying their life expectancy from diagnosis and
survival curves (86). In this scenario, there are several reasons
that may bring out the clinical or social need to reduce or stop
opioid pain therapy (87). Pain could reduce or completely remit
after an effective cancer cure, either from surgery or
radiotherapy, or pharmacological treatments. Sedation and other
opioid side effects could obstacles to work and activities resume;
indeed, long-term opioid therapies increase risks of abuse and
misuse.
Deprescription integrates opioid management expertise from
the prescribing schedule, to opioid therapy initiation, dose
titration, to switching or discontinuation, as reassumed in
Figure 3. Opioid tapering with the intention to discontinue
when side effects outweigh the benefits must always be
considered (87). As already addressed in the previous chapters,
protracted opioid use is associated with many adverse effects,
such as constipation, nausea and vomiting, daytime somnolence,
increased risk of falls, and poor concentration or memory loss. It
has also been high-lighted an increased mortality rate in patients
taking 100 mg/24 h of morphine or equivalent, compared with
doses equivalent low than 20 mg/24 h (87,88).
However, while the guidelines on the initiation and
management of cancer pain relief therapy with opioid are clear,
indications for the tapering of opioid therapy in cancer patients
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Frontiers in Pain Research 08 frontiersin.org

are very poor and often developed in the context of drug addiction
(89). Alongside the pharmacological strategies previously reported,
the literature suggests some fundamental principles that can be the
cornerstone of the correct management of this therapeutic phase,
reassumed in Table 1.
Clinicians should always work with patients and their
caregivers to define the best approach for pain management,
immediately establishing realistic goals, with a view to a shared
planning of the therapeutic path (90–92). Furthermore, risk
factors for developing analgesic dependence must be seriously
considered also for cancer patients, particularly when the disease
is in remission. If UOD emerges from the beginning of the
therapy in the general population suffering from chronic pain,
in cancer patients it is conceivable that the aspects of
psychological dependence emergemoreclearlyinthe
deprescribing process.
It is therefore essential, in the choice of pain-relief therapy, an
accurate clinical history that highlights the potential risk factors of
OUD. Furthermore, the role of the psychologist who can follow the
patient in the various phases of the disease and also in that of the
reduction of opioid therapy is fundamental. These factors may not
preclude the use of opioid therapy for pain, but their management
needs careful supervision (88).
Proper management of tapering of opioid in cancer patients
should be indeed based on five cardinal points (88):
1. Share the importance of reducing opioid with the patient,
according to the phase of the disease and the life-prolonging
therapies,
2. Involve the patient, giving him as much freedom as possible about
how to reduce opioid, with ongoing management and support,
3. Accurate and shared planning of the tapering until the
discontinuation,
4. Adopt multidisciplinary strategies for the management of
anxiety and related disorders,
5. Ensure the patient understands the difficulty of the pathway
and the need for support.
8. Conclusions
The clinical case that we presented allowed us to reflect on the
underestimated incidence of withdrawal syndrome in cancer
patients on long-term opioid therapy. In clinical practice, the
symptoms presented by the patient mimicked a cancer recurrence,
requiring an appropriate modification of the follow-up times and
involving an important amount of anxiety to the patient herself,
which a careful management of the opioid deprescribing process
would have avoided. Our findings are limited to a single case
report, that we used as a springboard for the whole work. It is a
limitation, nonetheless larger studies with a sufficient number of
patients are required to confirm that clonidine (or other α-agonist)
should be used in the withdrawal phase in patients treated with
opioid with cancer pain, not only in those with addiction.
In this narrative review, we summarized some aspects that are
relevant to the medical management of opioid treatment for cancer
pain. First, opioid withdrawal syndrome can mimic several
symptoms that are very common in cancer patients. We used a
scholarly case presentation of a patient with a history of metastatic
FIGURE 3
The journey of opioid prescription. At first, before prescription, the physician has to do a thorough assessment of the patient and the social context. The
prescription of the pain-relief therapy must follow the guidelines, considering the clinical characteristics of the patient and the localization of the disease.
Also, radiotherapy and physical rehabilitation have to be considered. The psychological aspects and non-pharmacological therapies should not be
underestimated. Equal attention must be given to the tapering of pain-relieving therapy: each step must be shared with the patient, who has to be
carefully monitored and instructed on the symptoms that may appear (i.e., hypertension, tachycardia, sweating, palpitations, …). A multidisciplinary
path involving oncologists and pain specialists, shared with the patient, can significantly reduce the risk of developing OUD for the patient, especially
in long survivors. Created with BioRender.com.
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Frontiers in Pain Research 09 frontiersin.org

sporadic paraganglioma, to underline the endocrine aspects of opioid
withdrawal syndrome. Moreover, in cancer patients, a high
psychological burden leads patients and physicians to underestimate
some distinctive symptoms of abstinence as asthenia and nausea.
The clinical case also allowed us also to highlight the lack of
guidelines on opioid tapering in cancer patients. Patients with
cancer pain clearly represent a different population from those with
chronic non-cancer pain, due to the evolutionary characteristics of
the underlying disease, which often lead to long-term therapy. One
of the fundamental reflections that emerge from our experience is
that the correct timing for reducing therapy must be identified
according to the patient, who has to be correctly informed about
the symptoms that may appear in this process. As is often done in
titration, even in the deprescribing it could be useful to create a
“therapeutic diary”for the patient, to report withdrawal symptoms.
Follow-up by the pain specialist should also be strictly timed.
In clinical practice, there are several tools that can help
physicians to unmask opioid withdrawal; nonetheless, none of
them is tailored to the patient that uses opioid to relief cancer
pain: an effort in this regard is suggested to the scientific
community of palliative specialists. These tools should be
validated not only for inpatients, but their use is “out”of the
hospitalization, at home, and pain management should be shared
with caregivers, nurses, and general practitioners: the awareness
of the pain and opioid use (and its withdrawal syndrome) should
be enriched in all clinical settings.
The most relevant food for thought that emerges with respect to the
management of this clinical case is the frequent lack of education of the
patient to promptly recognize withdrawal symptoms. Patients with
cancer are used to experiencing negative symptoms related to life-
prolonging treatments and therefore resilient towards the appearance
of even disturbing symptoms. In developing ad hoc guidelines for
opioid deprescribing, we deem it useful to suggest the creation of a
self-completion questionnaire for daily administration that allows the
patient to promptly identify the onset of withdrawal symptoms. It is
also essential to illustrate, share and agree from the beginning of
opioid tapering on the therapeutic attitude to maintain in the event
of the onset of symptoms: return to the previous dosage vs use of
drugs for symptom management vs. multimodal non-
pharmacologicalapproach.Thekeywordmustthereforebethe
sharing of decisions. Furthermore, the presence of a multidisciplinary
team is the added factor to optimize the patient management,
integrating moreover the outpatient approach with home service.
Data availability statement
The original contributions presented in the study are included
in the article/Supplementary Material, further inquiries can be
directed to the corresponding author.
Ethics statement
The studies involving humans were approved by Istituto
Oncologico Veneto Ethic Committee. The studies were conducted
in accordance with the local legislation and institutional
requirements. The participants provided their written informed
consent to participate in this study. Written informed consent was
obtained from the individual(s) for the publication of any
potentially identifiable images or data included in this article.
Author contributions
ER: Writing –original draft, Writing –review and editing.
AP: Writing –original draft, Writing –review and editing.
MC: Writing –original draft, Writing –review and editing.
GL: Writing –review and editing. IG: Writing –review and
editing. AB: Writing –review and editing. FC: Writing –
original draft, Writing –review and editing. FF: Writing –
review and editing.
Funding
The author(s) declare financial support was received for the
research, authorship, and/or publication of this article.
TABLE 1 Opioid deprescribing process: from risk factor to shared
decision.
Opioid deprescribing process in cancer patients: from risk
factor to shared decision
Risk factors of developing analgesic dependence
- previous personal or family history of addiction,
- reluctance to acknowledge psychological contributors to pain,
- significant psychiatric comorbidity
- social isolation
Potential obstacles: Potential facilitator:
- fear of pain recrudescence - stable family and friendly support
- fear of less effective non-opioid
analgesic drugs
- proper education in recognizing the side
effects of opioid,
- feeling of abandonment in the
deprescribing process,
- identify personal reasons that may affect
the route (i.e., work and driving
restrictions)
- limited availability and
affordability of health care.
- use of non-pharmacological therapies
Key principles of correct management of opioid deprescribing
1. share the importance of reducing opioid to the patient, according to the phase
of the disease and the life-prolonging therapies,
2. involve the patient with ongoing management and support,
3. outline ad accurate and shared tapering plan,
4. management of anxiety and related disorders,
5. ensure the patient understands the difficulty of the pathway and the need for
support.
Ruggiero et al. 10.3389/fpain.2023.1256809
Frontiers in Pain Research 10 frontiersin.org

The APC was funded by CDC 099045 (5x1000—AGON)
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated organizations,
or those of the publisher, the editors and the reviewers. Any product
that may be evaluated in this article, or claim that may be made by its
manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/fpain.2023.
1256809/full#supplementary-material
SUPPLEMENTARY TABLE 1
Timeline of oxycodone tapering compared with pain severity.
References
1. Raja SN, Carr DB, Cohen M, Finnerup NB, Flor H, Gibson S, et al. The revised
international association for the study of pain definition of pain: concepts, challenges,
and compromises. Pain. (2020) 161(9):1976–82. doi: 10.1097/j.pain.
0000000000001939
2. Caraceni A, Shkodra M. Cancer pain assessment and classification. Cancers
(Basel). (2019) 11(4):510. doi: 10.3390/cancers11040510
3. van den Beuken-van Everdingen MHJ, Hochstenbach LMJ, Joosten EAJ, Tjan-
Heijnen VCG, Janssen DJA. Update on prevalence of pain in patients with cancer:
systematic review and meta-analysis. J Pain Symptom Manage. (2016) 51
(6):1070–90.e9. doi: 10.1016/j.jpainsymman.2015.12.340
4. Ruggiero E, Tizianel I, Caccese M, Lombardi G, Pambuku A, Zagonel V, et al.
Advanced adrenocortical carcinoma: from symptoms control to palliative care.
Cancers (Basel). (2022) 14(23):5901. doi: 10.3390/cancers14235901
5. TERAPIA DEL DOLORE IN ONCOLOGIA—linee guida AIOM. (2021). Available
to: https://snlg.iss.it/wp-content/uploads/2022/06/LG-484-AIOM_Dolore.pdf
6. Caraceni A, Martini C, Zecca E, Fagnoni E. Cancer pain management and
palliative care. Handb clin neurol. Amsterdam, The Netherlands: Elsevier (2012).
p. 391–415. Available at: https://linkinghub.elsevier.com/retrieve/pii/B978044452138
500027X
7. Varrassi G, Coluzzi F, Guardamagna VA, Puntillo F, Sotgiu G, Vellucci R.
Personalizing cancer pain therapy: insights from the rational use of analgesics
(RUA) group. Pain Ther. (2021) 10(1):605–17. doi: 10.1007/s40122-021-00248-x
8. Ceccato F, Correa R, Livhits M, Falhammar H. Editorial: predictive tools in
pheochromocytoma and paraganglioma. Front Endocrinol (Lausanne). (2023)
14:13–5. doi: 10.3389/fendo.2023.1227543/full
9. Mercadante S. Cancer pain treatment strategies in patients with cancer. Drugs.
(2022) 82(13):1357–66. doi: 10.1007/s40265-022-01780-6
10. Corli O, Floriani I, Roberto A, Montanari M, Galli F, Greco MT, et al. Are strong
opioids equally effective and safe in the treatment of chronic cancer pain? A
multicenter randomized phase IV ‘real life’trial on the variability of response to
opioids. Ann Oncol. (2016) 27(6):1107–15. doi: 10.1093/annonc/mdw097
11. Mestdagh F, Steyaert A, Lavand’homme P. Cancer pain management: a narrative
review of current concepts, strategies, and techniques. Curr Oncol. (2023) 30
(7):6838–58. doi: 10.3390/curroncol30070500
12. Fallon M, Giusti R, Aielli F, Hoskin P, Rolke R, Sharma M, et al. Management of
cancer pain in adult patients: ESMO clinical practice guidelines. Ann Oncol. (2018) 29:
iv166–91. doi: 10.1093/annonc/mdy152
13. Aman MM, Mahmoud A, Deer T, Sayed D, Hagedorn JM, Brogan SE, et al. The
American society of pain and neuroscience (ASPN) best practices and guidelines for
the interventional management of cancer-associated pain. J Pain Res. (2021)
14:2139–64. doi: 10.2147/JPR.S315585
14. WHO Guidelines for the pharmacological and radiotherapeutic management of
cancer pain in adults and adolescents. Geneva, Switzerland: World Health
Organization (2018). Available at: https://www.ncbi.nlm.nih.gov/books/NBK537492/
(Cited September 7, 2023).
15. Caraceni A, Hanks G, Kaasa S, Bennett MI, Brunelli C, Cherny N, et al. Use of
opioid analgesics in the treatment of cancer pain: evidence-based recommendations from
the EAPC. Lancet Oncol. (2012) 13(2):e58–68. doi: 10.1016/S1470-2045(12)70040-2
16. Wiffen PJ, Wee B, Derry S, Bell RF, Moore RA. Opioids for cancer pain—an
overview of cochrane reviews. Cochrane Database Syst Rev. (2017) 2020(2). doi: 10.
1002/14651858.CD012592.pub2
17. Wiffen PJ, McQuay HJ. Oral morphine for cancer pain. In: Wiffen PJ, editors.
Cochrane database of systematic reviews. Chichester, UK: John Wiley & Sons, Ltd
(2007). doi: 10.1002/14651858.CD003868.pub2
18. Caraceni A, Pigni A, Brunelli C. Is oral morphine still the first choice opioid for
moderate to severe cancer pain? A systematic review within the European palliative
care research collaborative guidelines project. Palliat Med. (2011) 25(5):402–9.
doi: 10.1177/0269216310392102
19. Schmidt-Hansen M, Bromham N, Taubert M, Arnold S, Hilgart JS.
Buprenorphine for treating cancer pain. Cochrane Database Syst Rev. (2015) 2018
(12). doi: 10.1002/14651858.CD009596.pub4
20. Schmidt-Hansen M, Bennett MI, Arnold S, Bromham N, Hilgart JS, Page AJ,
et al. Oxycodone for cancer-related pain. Cochrane Database Syst Rev. (2022) 2022
(6). doi: 10.1002/14651858.CD003870.pub7
21. Nicholson AB, Watson GR, Derry S, Wiffen PJ. Methadone for cancer pain.
Cochrane Database Syst Rev. (2017) 2017(3). doi: 10.1002/14651858.CD003971.pub4
22. Wang D-D, Ma T-T, Zhu H-D, Peng C-B. Transdermal fentanyl for cancer pain:
trial sequential analysis of 3,406 patients from 35 randomized controlled trials.
J Cancer Res Ther. (2018) 14(8):14. doi: 10.4103/0973-1482.171368
23. Li Y, Ma J, Lu G, Dou Z, Knaggs R, Xia J, et al. Hydromorphone for cancer pain.
Cochrane Database Syst Rev. (2021) 2021(8). doi: 10.1002/14651858.CD011108.pub3
24. Paice JA, Bohlke K, Barton D, Craig DS, El-Jawahri A, Hershman DL, et al. Use
of opioids for adults with pain from cancer or cancer treatment: ASCO guideline.
J Clin Oncol. (2023) 41(4):914–30. doi: 10.1200/JCO.22.02198
25. Hughes LT, Raftery D, Coulter P, Laird B, Fallon M. Use of opioids in patients
with cancer with hepatic impairment—a systematic review. BMJ Support Palliat Care.
(2022) 12(2):152–7. doi: 10.1136/bmjspcare-2021-003065
26. Klepstad P, Kaasa S, Borchgrevink PC. Starting step III opioids for moderate to
severe pain in cancer patients: dose titration: a systematic review. Palliat Med. (2011)
25(5):424–30. doi: 10.1177/0269216310386280
27. Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC clinical practice
guideline for prescribing opioids for pain—United States, 2022. MMWR Recomm
Rep. (2022) 71(3):1–95. doi: 10.15585/mmwr.rr7103a1
28. Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N, et al.
Opioid complications and side effects. Pain Physician. (2008) 11(2 Suppl):S105–20.
doi: 10.36076/ppj.2008/11/S105
29. Collett BJ. Opioid tolerance: the clinical perspective. Br J Anaesth. (1998) 81
(1):58–68. doi: 10.1093/bja/81.1.58
30. Greene MS, Chambers RA. Pseudoaddiction: fact or fiction? An investigation of
the medical literature. Curr Addict Rep. (2015) 2(4):310–7. doi: 10.1007/s40429-015-
0074-7
31. Swegle JM, Logemann C. Management of common opioid-indu ced adverse
effects. Am Fam Physician. (2006) 74(8):1347–54.
32. Kurz A, Sessler DI. Opioid-induced bowel dysfunction. Drugs. (2003) 63
(7):649–71. doi: 10.2165/00003495-200363070-00003
Ruggiero et al. 10.3389/fpain.2023.1256809
Frontiers in Pain Research 11 frontiersin.org

33. Herndon CM, Jackson KC, Hallin PA. Management of opioid-induced
gastrointestinal effects in patients receiving palliative care. Pharmacotherapy. (2002)
22(2):240–50. doi: 10.1592/phco.22.3.240.33552
34. De Schepper HU, Cremonini F, Park M-I, Camilleri M. Opioids and the gut:
pharmacology and current clinical experience. Neurogastroenterol Motil. (2004) 16
(4):383–94. doi: 10.1111/j.1365-2982.2004.00513.x
35. Meissner W, Schmidt U, Hartmann M, Kath R, Reinhart K. Oral naloxone
reverses opioid-associated constipation. Pain. (2000) 84(1):105–9. doi: 10.1016/
S0304-3959(99)00185-2
36. Prichard D, Norton C, Bharucha AE. Management of opioid-induced
constipation. Br J Nurs. (2016) 25(10):S4–11. doi: 10.12968/bjon.2016.25.10.S4
37. Smith HS, Laufer A. Opioid induced nausea and vomiting. Eur J Pharmacol.
(2014) 722:67–78. doi: 10.1016/j.ejphar.2013.09.074
38. Nicholson BD. Economic and clinical burden of opioid-induced nausea and
vomiting. Postgrad Med. (2017) 129(1):111–7. doi: 10.1080/00325481.2017.1243004
39. Cepeda M. Side effects of opioids during short-term administration: effect of age,
gender, and race. Clin Pharmacol Ther. (2003) 74(2):102–12. doi: 10.1016/S0009-9236
(03)00152-8
40. Suh D-C, Kim MS, Ch ow W, Jang E-J. Use of medications and resources for
treatment of nausea, vomit ing, or constipation in ho spitalized patients treated
with analgesics. Clin J Pain. (2011) 27(6):508–17. doi: 10.1097/AJP.
0b013e31820d9b76
41. Sampaio-Cunha TJ, Martins I. Knowing the enemy is halfway towards victory: a
scoping review on opioid-induced hyperalgesia. J Clin Med. (2022) 11(20):6161.
doi: 10.3390/jcm11206161
42. Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. A comprehensive
review of opioid-induced hyperalgesia. Pain Physician. (2011) 14(2):145–61. doi: 10.
36076/ppj.2011/14/145
43. Mercadante S, Arcuri E. Hyperalgesia and opioid switching. Am J Hosp Palliat
Med. (2005) 22(4):291–4. doi: 10.1177/104990910502200411
44. Ramasubbu C, Gupta A. Pharmacological treatment of opioid-induced
hyperalgesia: a review of the evidence. J Pain Palliat Care Pharmacother. (2011) 25
(3):219–30. doi: 10.3109/15360288.2011.589490
45. Roeckel L-A, Le Coz G-M, Gavériaux-Ruff C, Simonin F. Opioid-induced
hyperalgesia: cellular and molecular mechanisms. Neuroscience. (2016) 338:160–82.
doi: 10.1016/j.neuroscience.2016.06.029
46. Urits I, Patel A, Zusman R, Virgen CG, Mousa M, Berger AA, et al. A
comprehensive update of lofexidine for the management of opioid withdrawal
symptoms. Psychopharmacol Bull. (2020) 50(3):76–96.
47. The ASAM national practice guideline for the treatment of opioid use disorder:
2020 focused update. J Addict Med. (2020) 14(2S):1–91. doi: 10.1097/ADM.
0000000000000633
48. Kreek MJ, Reed B, Butelman ER. Current status of opioid addiction treatment
and related preclinical research. Sci Adv. (2019) 5(10). doi: 10.1126/sciadv.aax9140
49. WHO. International statistical classification of diseases and related health
problems, 10th revision. Geneva, Switzerland: World Health Organization (2016).
50. Srivastava AB, Mariani JJ, Levin FR. New directions in the treatment of opioid
withdrawal. Lancet (London, England). (2020) 395(10241):1938–48. doi: 10.1016/
S0140-6736(20)30852-7
51. Dowell D, Compton WM, Giroir BP. Patient-Centered reduction or
discontinuation of long-term opioid analgesics. JAMA. (2019) 322(19):1855. doi: 10.
1001/jama.2019.16409
52. Guidance for opioid reduction in primary care. (2020). Available at:
Guidance for opioid reduction in primary care—JQ/HW clinical leads (Cited
April 15, 2023).
53. Mazei-Robison MS, Nestler EJ. Opiate-induced molecular and cellular plasticity
of ventral tegmental area and locus coeruleus catecholamine neurons. Cold Spring
Harb Perspect Med. (2012) 2(7):a012070. doi: 10.1101/cshperspect.a012070
54. TR K. Neurobiology of abused drugs. J Nerv Ment Dis. (1990) 178(4):217–27.
doi: 10.1097/00005053-199004000-00001
55. Kosten T, George T. The neurobiology of opioid dependence: implications for
treatment. Sci Pract Perspect. (2002) 1(1):13–20. doi: 10.1151/spp021113
56. Kosten TR, Baxter LE. Review article: effective management of opioid
withdrawal symptoms: a gateway to opioid dependence treatment. Am J Addict.
(2019) 28(2):55–62. doi: 10.1111/ajad.12862
57. Peachey JE, Lei H. Assessment of opioid dependence with naloxone. Br J Addict.
(1988) 83(2):193–201. doi: 10.1111/j.1360-0443.1988.tb03981.x
58. Wesson DR, Ling W. The clinical opiate withdrawal scale (COWS).
J Psychoactive Drugs. (2003) 35(2):253–9. doi: 10.1080/02791072.2003.10400007
59. Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD.
Two new rating scales for opiate withdrawal. Am J Drug Alcohol Abuse. (1987) 13
(3):293–308. doi: 10.3109/00952998709001515
60. Alawa J, Muhammad M, Kazemitabar M, Bromberg DJ, Garcia D, Khoshnood
K, et al. Medication for opioid use disorder in the Arab world: a systematic review. Int
J Drug Policy. (2022) 102:103617. doi: 10.1016/j.drugpo.2022.103617
61. Ling W, Charuvastra C, Collins JF, Batki S, Brown LS, Kintaudi P, et al.
Buprenorphine maintenance treatment of opiate dependence: a multicenter,
randomized clinical trial. Addiction. (1998) 93(4):475–86. doi: 10.1046/j.1360-0443.
1998.9344753.x
62. Oesterle TS, Thusius NJ, Rummans TA, Gold MS. Medication-assisted treatment
for opioid-use disorder. Mayo Clin Proc. (2019) 94(10):2072–86. doi: 10.1016/j.
mayocp.2019.03.029
63. Blanco C, Volkow ND. Management of opioid use disorder in the USA: present
status and future directions. Lancet. (2019) 393(10182):1760–72. doi: 10.1016/S0140-
6736(18)33078-2
64. Dematteis M, Auriacombe M, D’Agnone O, Somaini L, Szerman N, Littlewood
R, et al. Recommendations for buprenorphine and methadone therapy in opioid use
disorder: a European consensus. Expert Opin Pharmacother. (2017) 18(18):1987–99.
doi: 10.1080/14656566.2017.1409722
65. Gowing L, Farrell M, Ali R, White JM. Alpha 2 -adrenergic agonists for the
management of opioid withdrawal. Cochrane Database Syst Rev. (2016):18. doi: 10.
1002/14651858.CD002024.pub5
66. Shulman M, Wai JM, Nunes E V. Buprenorphine treatment for opioid use
disorder: an overview. CNS Drugs. (2019) 33(6):567–80. doi: 10.1007/s40263-019-
00637-z
67. J JAFFE. From morphine clinics to buprenorphine: regulating opioid agonist
treatment of addiction in the United States. Drug Alcohol Depend. (2003) 70(2):
S3–11. doi: 10.1016/S0376-8716(03)00055-3
68. Gowing L, Ali R, White JM, Mbewe D. Buprenorphine for managing opioid
withdrawal. Cochrane Database Syst Rev. (2017) 2017(2). doi: 10.1002/14651858.
CD002025.pub5
69. Kleber HD. Pharmacologic treatments for opioid dependence: detoxification and
maintenance options. Dialogues Clin Neurosci. (2007) 9(4):455–70. doi: 10.31887/
DCNS.2007.9.2/hkleber
70. Ignar DM, Kuhn CM. Effects of specific mu and kappa opiate tolerance and
abstinence on hypothalamo-pituitary-adrenal axis secretion in the rat. J Pharmacol
Exp Ther. (1990) 255(3):1287–95.
71. Solecki WB, Kus N, Gralec K, Klasa A, Pradel K, Przewłocki R. Noradrenergic
and corticosteroid receptors regulate somatic and motivational symptoms of
morphine withdrawal. Behav Brain Res. (2019) 360(October 2018):146–57. doi: 10.
1016/j.bbr.2018.11.041
72. James MH, Stopper CM, Zimmer BA, Koll NE, Bowrey HE, Aston-Jones G.
Increased number and activity of a lateral subpopulation of hypothalamic orexin/
hypocretin neurons underlies the expression of an addicted state in rats. Biol
Psychiatry. (2019) 85(11):925–35. doi: 10.1016/j.biopsych.2018.07.022
73. McGregor R, Wu M-F, Holmes B, Lam HA, Maidment NT, Gera J, et al.
Hypocretin/orexin interactions with norepinephrine contribute to the opiate
withdrawal syndrome. J Neurosci. (2022) 42(2):255–63. doi: 10.1523/JNEUROSCI.
1557-21.2021
74. Drake CT, Aicher SA, Montalmant FL, Milner TA. Redistribution of mu-opioid
receptors in C1 adrenergic neurons following chronic administration of morphine.
Exp Neurol. (2005) 196(2):365–72. doi: 10.1016/j.expneurol.2005.08.012
75. Fitzgerald PJ. Many drugs of abuse may be acutely transformed to dopamine,
norepinephrine and epinephrine in vivo. Int J Mol Sci. (2021) 22(19). doi: 10.3390/
ijms221910706
76. Zhang GF, Ren YP, Sheng LX, Chi Y, Du WJ, Guo S, et al. Dysfunction of the
hypothalamic-pituitary-adrenal axis in opioid dependent subjects: effects of acute and
protracted abstinence. Am J Drug Alcohol Abuse. (2008) 34(6):760–8. doi: 10.1080/
00952990802385781
77. Ceccato F, Scaroni C. Central adrenal insufficiency: open issues regarding
diagnosis and glucocorticoid treatment. Clin Chem Lab Med. (2019) 57(8):1125–35.
doi: 10.1515/cclm-2018-0824
78. Schluger JH, Borg L, Ho A, Kreek MJ. Altered HPA axis responsivity to
metyrapone testing in methadone maintained former heroin addicts with ongoing
cocaine addiction. Neuropsychopharmacology. (2001) 24(5):568–75. doi: 10.1016/
S0893-133X(00)00222-0
79. Kienbaum P, Thurauf N, Michel MC, Scherbaum N, Gastpar M, Peters J.
Profound increase in epinephrine concentration in plasma and cardiovascular
stimulation after [micro sign]-opioid receptor blockade in opioid-addicted patients
during barbiturate-induced anesthesia for acute detoxification. Anesthesiology.
(1998) 88(5):1154–61. doi: 10.1097/00000542-199805000-00004
80. Kienbaum P, Heuter T, Michel MC, Scherbaum N, Gastpar M, Peters J.
Sympathetic neural activation evoked by μ-receptor blockade in patients addicted to
opioids is abolished by intravenous clonidine. Anesthesiology. (2002) 96(2):346–51.
doi: 10.1097/00000542-200202000-00020
81. Gerra G, Ceresini S, Esposito A, Zaimovic A, Moi G, Bussandri M, et al.
Neuroendocrine and behavioural responses to opioid receptor-antagonist during
Ruggiero et al. 10.3389/fpain.2023.1256809
Frontiers in Pain Research 12 frontiersin.org

heroin detoxification: relationship with personality traits. Int Clin Psychopharmacol.
(2003) 18(5):261–9. doi: 10.1097/00004850-200309000-00002
82. Laina A, Latsios G, Dri E, Aggeli C, Tsiamis E, Tsioufis K. Buprenorphine
withdrawal induced takotsubo cardiomyopathy: a series of unfortunate events.
J Cardiol Cases. (2022) 25(5):316–8. doi: 10.1016/j.jccase.2021.11.012
83. Spadotto V, Zorzi A, ElMaghawry M, Meggiolaro M, Pittoni GM. Heart failure
due to ’stress cardiomyopathy’: a severe manifestation of the opioid withdrawal
syndrome. Eur Hear J Acute Cardiovasc Care. (2013) 2(1):84–7. doi: 10.1177/
2048872612474923
84. Wang Y, Yu X, Huang Y. Predictive factors for catecholamine-induced
cardiomyopathy in patients with pheochromocytoma and paraganglioma. Front
Endocrinol (Lausanne). (2022) 13. doi: 10.3389/fendo.2022.853878/full
85. Remde H, Pamporaki C, Quinkler M, Nölting S, Prejbisz A, Timmers HJLM,
et al. Improved diagnostic accuracy of clonidine suppression testing using an age-
related cutoff for plasma normetanephrine. Hypertension. (2022) 79(6):1257–64.
doi: 10.1161/HYPERTENSIONAHA.122.19019
86. Forman D, Gatta G, Capocaccia R, Janssen-Heijnen ML, Coebergh JW. Cancer
survival. Lancet. (2001) 357(9255):555. doi: 10.1016/S0140-6736(05)71700-1
87. Hamilton M, Gnjidic D, Christine Lin C-W, Jansen J, Weir KR, Shaheed CA, et al.
Opioid deprescribing: qualitative perspectives from those with chronic non-cancer pain.
Res Soc Adm Pharm. (2022) 18(12):4083–91. doi: 10.1016/j.sapharm.2022.07.043
88. Heartshorne R. Dose reduction of long-term opioids: our duty as clinicians. Br
J Gen Pract. (2019) 69(681):191. doi: 10.3399/bjgp19X701957
89. Sandhu H, Underwood M, Furlan A, Noyes J, Eldabe S. What interventions are
effective to taper opioids in patients with chronic pain? Br Med J. (2018) 362:k2990.
doi: 10.1136/bmj.k2990
90. Emery J, Butow P, Lai-Kwon J, Nekhlyudov L, Rynderman M, Jefford M.
Management of common clinical problems experienced by survivors of cancer.
Lancet. (2022) 399(10334):1537–50. doi: 10.1016/S0140-6736(22)00242-2
91. Paice JA, Portenoy R, Lacchetti C, Campbell T, Cheville A, Citron M, et al.
Management of chronic pain in survivors of adult cancers: american society of
clinical oncology clinical practice guideline. J Clin Oncol. (2016) 34(27):3325–45.
doi: 10.1200/JCO.2016.68.5206
92. Koyyalagunta D, Bruera E, Solanki DR, Nouri KH, Burton AW, Toro MP, et al.
A systematic review of randomized trials on the effectiveness of opioids for cancer
pain. Pain Physician. (2012) 15(3 Suppl):ES39–58. doi: 10.36076/ppj.2012/15/ES39
Ruggiero et al. 10.3389/fpain.2023.1256809
Frontiers in Pain Research 13 frontiersin.org