Longer-term pain and drug management

Agent report for Kya, 10 September 2026. Every PMID was checked on PubMed E-utilities today; anything unchecked is labelled. L1 systematic review or guideline on RCTs, L2 RCT, L3 cohort or case-control, L4 case series, L5 expert opinion. No trial population is skull-base chordoma. No prognosis content. Not medical advice.

Facts used: woman, 34, 51 kg, clival chordoma, right trigeminal pain 12 to 14 months, III, IV and VI palsies; MR morphine 20 mg bd, Oramorph 10 mg 3 to 5 times a day, gabapentin 300 mg bd, diclofenac, paracetamol, melatonin, senna; surgery and proton therapy in 2 to 8 months.

1. Opioid dose: where 40 mg a day sits

• Start range. NICE CG140 (2012, updated 2016, sections 1.1.4 to 1.1.9), EAPC (Caraceni 2012, Lancet Oncology, PMID 22300860, L1) and ESMO (Fallon 2018, Annals of Oncology, PMID 30052758, L1) all start oral morphine at 20 to 30 mg a day regular plus 5 mg rescue. The patient's 40 mg a day is one step above a starting dose: low-to-moderate. For scale, advanced-cancer patients in one trial averaged 160 to 270 mg oral morphine equivalent a day (Paulsen 2014, JCO, PMID 25002731, L2).
• No ceiling. Strong opioids have no pharmacological maximum; side effects and diminishing benefit set the limit (CG140; EAPC 2012). About 19 in 20 cancer patients get pain to mild or none on oral opioids, low-quality evidence (Wiffen 2017, PMID 28683172, L1).
• Escalation. Raise the regular dose by 30 to 50 percent when pain is uncontrolled, no more often than every 24 hours for MR morphine (ESMO 2018 titration section; CG140 1.1.9). For the patient: 20 mg bd to 30 mg bd, then 40 mg bd.
• Folding in breakthrough. Rescue dose is about one sixth of the 24-hour regular dose (Davies 2009, European Journal of Pain, PMID 18707904, L1 consensus; EAPC 2012). If 3 or more rescues are needed most days, the 24-hour total (regular plus rescue) becomes the new regular dose, split in two, and the rescue dose is recalculated. The patient today: 40 plus 30 to 50 mg = 70 to 90 mg a day, pointing to MR morphine 35 to 45 mg bd with rescue 10 to 15 mg.
• Diminishing returns and opioid-induced hyperalgesia. Tolerance is expected over months. OIH is different: the opioid itself makes the nervous system more pain-sensitive, so pain spreads and worsens as the dose rises. Confirmed on long-term opioids, weaker in pain patients than in opioid use disorder (Higgins 2019, BJA, PMID 30915985, L1; review Mercadante 2019, CNS Drugs, PMID 31578704, L5). Two rises with no better relief, or worse pain after a rise, means rotate or add an adjuvant, not escalate (ESMO 2018).

2. Opioid rotation

• When. Side effects intolerable, or dose rises no longer help (EAPC 2012; ESMO 2018).
• Evidence. No RCTs; case series report improvement in most patients (Quigley 2004, Cochrane, PMID 15266542, L4). Ratios come from the EAPC review of 31 prospective studies (Mercadante 2011, Palliative Medicine, PMID 21708857, L1); published ranges are wide (Davis 2024, PMID 39046534, L1).
• Ratios, oral morphine to new drug: oxycodone 1.5:1 (60 mg = 40 mg); hydromorphone 5:1 (60 mg = 12 mg); fentanyl patch 100:1 (60 mg a day = 25 micrograms per hour); buprenorphine patch about 75:1; methadone 5:1 to 10:1, unpredictable.
• The 25 to 50 percent cut. Cross-tolerance is incomplete, so the calculated new dose is cut by 25 to 50 percent and re-titrated with rescue doses (EAPC 2012; ESMO 2018).
• Drug by drug. Oxycodone (Schmidt-Hansen 2017, Cochrane, PMID 28829910, L1) and hydromorphone (Bao 2016, Cochrane, PMID 27727452, L1) match morphine. Fentanyl patch: similar relief, less constipation (Hadley 2013, Cochrane, PMID 24096644, L1), stable pain only. Methadone: as effective as morphine, NMDA action may help nerve pain, but its long variable half-life makes it a specialist drug ( 2017, Cochrane, PMID 28177515, L1; Mercadante 2018, PMID 29101087, L1).

3. Neuropathic adjuvants

• Order of use. NeuPSIG (Finnerup 2015, Lancet Neurology, PMID 25575710, L1): tricyclics NNT 3.6, duloxetine 6.4, gabapentin 7.2, pregabalin 7.7 first line; strong opioids NNT 4.3 but third line.
• Gabapentin titration. Licensed maximum 3,600 mg a day in three doses; absorption falls from about 60 percent at 900 mg to about 33 percent at 3,600 mg (Neurontin SmPC), so benefit flattens beyond about 1,800 to 2,400 mg. The cancer trial titrated 600 to 1,800 mg on top of opioids and cut average pain from 5.4 to 4.6 out of 10, 7.6 percent stopping for side effects (Caraceni 2004, JCO, PMID 15254060, L2). Cochrane: 3 to 4 in 10 get substantial relief at 1,200 mg or more versus 1 to 2 in 10 on placebo, NNT 6.7 (Wiffen 2017, PMID 28597471, L1). Fair trial: 2 to 4 weeks at 900 to 1,800 mg; if nothing, stop. Schedule in thread 14.
• Pregabalin. Twice daily, linear absorption, 150 to 600 mg a day; NNT 7.7 at 600 mg (Derry 2019, Cochrane, PMID 30673120, L1). In 120 cancer neuropathic pain patients it beat amitriptyline, gabapentin and placebo and cut morphine use (Mishra 2012, PMID 21745832, L2, single centre). The swap if gabapentin fails.
• Amitriptyline or nortriptyline. 10 to 75 mg at night; Cochrane found no unbiased evidence of benefit but did not show it ineffective (Moore 2015, PMID 26146793, L1). Nortriptyline is less sedating (clinical judgement); anticholinergic and cardiac caution.
• Duloxetine. 60 mg a day, NNT 5 to 6 in diabetic neuropathy (Lunn 2014, Cochrane, PMID 24385423, L1); RCT benefit in chemotherapy neuropathy (Smith 2013, JAMA, PMID 23549581, L2).
• Carbamazepine and oxcarbazepine. First line for classical trigeminal neuralgia at 200 to 1,200 and 300 to 1,800 mg a day (Bendtsen 2019, EAN guideline, PMID 30860637, L1); Cochrane grades the evidence low (Wiffen 2014, PMID 24719027, L1). Caveats: the patient's pain is continuous with flares, not pure second-long shocks; tumour-caused neuralgia responds to drugs at first but tumour removal is the fix (Cheng 1993, PMID 8232946, L3); carbamazepine causes dizziness, diplopia and unsteadiness that would muddle her eye observations, induces liver enzymes and can drop sodium. If shocks appear, oxcarbazepine is cleaner. Flare rescue: Moore 2019, BJA, PMID 31208761, L1.
• Dexamethasone for nerve compression. ESMO 2018 and EAPC support a short course. Cochrane: low-quality evidence of modest benefit at one week (Haywood 2015, PMID 25908299, L1). The best RCT, methylprednisolone 32 mg a day for 7 days on top of opioids, gave no extra analgesia but better fatigue and appetite (Paulsen 2014, PMID 25002731, L2). Conditions: steroids before biopsy can shrink lymphoma and spoil histology (thread 02), so timing is the team's call; courses beyond 1 to 2 weeks bring sleep, mood, sugar and muscle problems.

4. Specialist and interventional options

• Who. Complex cancer pain belongs with the hospital pain team and palliative (supportive) care together; the referral is a symptom-control tool, not a statement about outlook. Early palliative care improves quality of life and mood (Temel 2010, NEJM, PMID 20818875, L2; Haun 2017, Cochrane, PMID 28603881, L1).
• Ketamine. Cochrane: insufficient evidence (Bell 2017, PMID 28657160, L1). The large RCT of subcutaneous ketamine added to opioids showed no benefit (31 vs 27 percent response), NNT 25, NNH 6 (Hardy 2012, JCO, PMID 22965960, L2). Last resort, specialist only.
• Intravenous lidocaine. 26 studies: relief in the hours after infusion (12 points of 100), nothing lasting, side effects far commoner than placebo (OR 7.8) but rarely serious (Zhu 2019, PMID 31620064, L1). A bridge, not a plan.
• Sphenopalatine ganglion block. Transnasal local anaesthetic or neurolytic block for head and neck cancer face pain: repeated case series, relief lasting days to months (Varghese 2002, PMID 12380665, L4; Pena 2019, PMID 31609721, L4; review Smith 2025, PMID 41396338, L5). Low risk, repeatable, the first block to ask about.
• Gasserian ganglion procedures. Radiofrequency of the ganglion is long established for tic pain (Sweet 1976, PMID 975705, L4) with small recent cancer series (Ahuactzin 2025, PMID 39906438, L4). A 2026 systematic review of nerve procedures in head and neck cancer: 28 studies, 536 patients, mostly case reports, no major complications reported, very low-quality evidence (Fujimura 2026, PMID 42233128, L1 of L4 data). Caveat: the needle passes the foramen ovale into Meckel's cave, beside a tumour already in the cavernous sinus and against the carotid; only an interventional pain consultant with the images can say whether it is safe. Gabapentin first is reasonable.

5. Safety over months

• Constipation ladder. Regular, not as-needed: stimulant (senna) plus osmotic (macrogol) from day one, raised with the opioid (Larkin 2018, ESMO, PMID 30016389, L1; Candy 2015, Cochrane, PMID 25967924, L1, no laxative superior). If laxatives fail: naloxegol 12.5 to 25 mg daily (NICE TA345) or methylnaltrexone, which reverse gut effects without reversing analgesia (Candy 2018, Cochrane, PMID 29869799, L1; naloxegol 44 vs 29 percent response, Chey 2014, NEJM, PMID 24896818, L2).
• Nausea and sedation. Both usually fade within 1 to 2 weeks of a change; persistent nausea gets metoclopramide or haloperidol (EAPC 2012). Cognition on a stable dose is only mildly affected, on weak studies (Mailis-Gagnon 2012, PMID 22673489, L1); the week after each rise is the risky window (thread 08).
• Gabapentinoid plus opioid. MHRA Drug Safety Update, October 2017: gabapentin and pregabalin add to opioid respiratory depression. Co-prescription raised the odds of opioid-related death by about 50 percent (adjusted OR 1.49; 1.58 at 1,800 mg or more) (Gomes 2017, PLoS Medicine, PMID 28972983, L3). Absolute risk at the patient's doses is small; no alcohol or sedatives, slow gabapentin steps, someone aware at night after each change.
• Driving. Road Traffic Act 1988 section 5A: blood morphine above 80 micrograms per litre is an offence; section 5A(3) gives a medical defence if prescribed, taken as directed and not impaired, but the section 4 impairment offence still applies. DVLA bars driving with uncontrolled diplopia, so the patient must not drive now for the eye reason alone; later, a stable dose does not bar driving, but carry the prescription and never drive in the days after a dose change.
• Tolerance, dependence, addiction. Tolerance and physical dependence (withdrawal if stopped) are expected pharmacology, not addiction; addiction is compulsive use despite harm, uncommon in cancer pain without prior substance problems, never zero, somewhat higher in younger adults (Ballantyne 2003, NEJM, PMID 14614170, L5). One prescriber, MR opioid as backbone, rescues counted in the diary, taper plan written before surgery.

6. Tapering after definitive treatment

• Opioids. After resection and proton therapy, pain should fall and the dose follows. After months of use: reduce 5 to 20 percent every 2 to 4 weeks, slower near the end; 10 percent a week if use was only weeks (VA/DoD 2022, Sandbrink 2023, Annals of Internal Medicine, PMID 36780654, L1; NICE NG215, 2022, section 1.5; Opioids Aware). Pain and function often improve with supported reduction (Frank 2017, Annals of Internal Medicine, PMID 28715848, L1). Withdrawal (sweating, cramps, diarrhoea, anxiety, insomnia, restless legs) means the step was too big: go back one step and hold.
• Gabapentin. Abrupt stopping after months causes agitation, insomnia, sweating and rarely seizures, 12 hours to 7 days after the last dose (Mersfelder 2016, PMID 26721643, L1 review of cases). SmPC minimum one week; after months, 300 mg steps every 3 to 7 days (clinical judgement).
• Persistent pain after skull-base treatment. Post-craniotomy headache in 40 percent at 6 months, 29 percent chronic (Rocha-Filho 2008, Cephalalgia, PMID 17986272, L3, 79 aneurysm patients). After endoscopic endonasal surgery the main complaints are nasal crusting, smell loss and sinus discomfort, improving over 3 to 6 months (Hegde 2023, PMID 38102512, L3). After proton therapy in 100 chordoma patients: acute grade 3 pain in 3, late headache in 2 (Chhabra 2023, Radiotherapy and Oncology, PMID 36813169, L3). Nerve pain present before surgery can outlast the tumour if the nerve is damaged; compression pain usually improves as the mass comes off the nerve, but nobody can promise it.

7. Chordoma and skull-base pain data

• Headache and diplopia (usually VI) are the commonest presenting features of clival chordoma; trigeminal pain is less common and points to cavernous sinus or Meckel's cave involvement (no percentages verified today).
• Tumours caused about 10 percent of trigeminal neuralgia in a large referral series (296 of 2,972); those patients were younger, drugs helped at first, tumour removal relieved the pain (Cheng 1993, PMID 8232946, L3).
• New cranial nerve deficits: 6.7 percent after endoscopic endonasal chordoma resection in 60 patients (Koutourousiou 2012, Neurosurgery, PMID 22592328, L4); permanent new deficit 28.6 percent with open craniocervical approaches (Colli 2001, J Neurosurg, PMID 11765837, L4); cranial nerve impairment the commonest complication in 71 clival cases (Sen 2010, J Neurosurg, PMID 19929198, L4). None reports pain scores, and no chordoma trial has pain as an endpoint; pain response is inferred from tumour-compression pain in general.

Sources without a PMID, cited from knowledge of the documents and not re-fetched: NICE CG140, NG215, TA345; MHRA Drug Safety Update October 2017; Road Traffic Act 1988 s5A; DVLA Assessing fitness to drive; Neurontin SmPC; Opioids Aware.